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CREB3L3c.313G>ABenign
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Variant interpretation report

CREB3L3 c.313G>A, p.(Gly105Arg)

NM_032607.3:c.313G>A NP_115996.1:p.(Gly105Arg) View identifiers
Classification
Benign

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.

Benign.A benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About CREB3L3

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 0 Benign evidence criteria: 3
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 3
BA1Stand alone
BA1 · stand alone

This variant is too common for a rare pathogenic variant under the default non-VCEP benign stand-alone threshold. The East Asian allele frequency is 3.44274% in gnomAD v2.1 and 3.43413% in gnomAD v4.1, which are both above the BA1 threshold of 1.0%.

BS1Strong
BS1 · strong

This variant is more frequent than expected for a pathogenic CREB3L3 variant under the default non-VCEP strong benign frequency threshold. The East Asian allele frequency is 3.44274% in gnomAD v2.1 and 3.43413% in gnomAD v4.1, which are both above the BS1 threshold of 0.3%.

BP4Supporting
BP4 · supporting

Multiple computational results support a benign interpretation rather than a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, REVEL is 0.257, and BayesDel is -0.423809.

Recorded classification: Benign

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BA1 stand-alone benign, BS1 strong benign, BP4 supporting benign; combination = 1 stand-alone benign, which maps to Benign.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
3,478 / 1,613,834 alleles

gnomAD v4.1: 3,478 / 1,613,834 alleles. Recorded AF 0.00215512. Recorded homozygote count 37.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.0037177; MAF= 0.37177%, 1047/281626 alleles, homozygotes = 14) and has highest observed frequency in the East Asian population (AF= 0.0344274; MAF= 3.44274%, 686/19926 alleles, homozygotes = 13); grpmax FAF= 0.0321736.

Applied · BA1, BS1 →
gnomAD v4.1 ↗gnomAD v2.1 ↗
No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

Applied · BP4 →
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

28 criteria with recorded statuses: 3 met · 2 not met · 19 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The CREB3L3 c.313G>A (p.Gly105Arg, p.G105R) variant has been reported in ClinVar as Benign with criteria provided by a single submitter representing 2 clinical laboratory submissions.

This variant is common in population databases, with gnomAD v2.1 showing a total allele frequency of 0.37177% and an East Asian allele frequency of 3.44274%, and gnomAD v4.1 showing a total allele frequency of 0.21551% and an East Asian allele frequency of 3.43413%, which is above the default benign population thresholds.

Computational evidence does not support a damaging effect, with SpliceAI predicting no significant splice impact (maximum delta score 0.02), REVEL 0.257, and BayesDel -0.423809.

Met · 3

BA1 Stand aloneThis variant is too common for a rare pathogenic variant under the default non-VCEP benign stand-alone threshold. The East Asian allele frequency is 3.44274% in gnomAD v2.1 and 3.43413% in gnomAD v4.1, which are both above the BA1 threshold of 1.0%. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 East Asian AF 0.0344274
  • gnomAD v4.1 East Asian AF 0.0343413
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 StrongThis variant is more frequent than expected for a pathogenic CREB3L3 variant under the default non-VCEP strong benign frequency threshold. The East Asian allele frequency is 3.44274% in gnomAD v2.1 and 3.43413% in gnomAD v4.1, which are both above the BS1 threshold of 0.3%. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 East Asian AF 0.0344274
  • gnomAD v4.1 East Asian AF 0.0343413
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 SupportingMultiple computational results support a benign interpretation rather than a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, REVEL is 0.257, and BayesDel is -0.423809. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.02
  • REVEL score 0.257
  • BayesDel score -0.423809
Sources
spliceai ↗revelbayesdel

Not met · 2 · evaluated, threshold not reached

PM2 This variant is not absent from population databases and is not rare by generic non-VCEP thresholds. In gnomAD v2.1 the total allele frequency is 0.37177% and the East Asian allele frequency is 3.44274%, and in gnomAD v4.1 the total allele frequency is 0.21551% and the East Asian allele frequency is 3.43413%; these values are above the default PM2 threshold of 0.1%. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 total AF 0.0037177
  • East Asian AF 0.0344274
  • gnomAD v4.1 total AF 0.00215512
  • East Asian AF 0.0343413
Sources
gnomad_v2 ↗gnomad_v4 ↗
PP3 Available computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, REVEL is 0.257, and BayesDel is -0.423809, which do not provide supportive evidence for pathogenicity. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.02
  • REVEL score 0.257
  • BayesDel score -0.423809
Sources
spliceai ↗revelbayesdel

Not assessed · 19 · no assessment recorded

PS1 No evidence was identified showing that a different nucleotide change causing the same amino acid substitution has already been established as pathogenic or likely pathogenic. Details ▾Hide ▴
Still missing
  • Same-amino-acid pathogenic comparison was not identified
PS2 No confirmed de novo occurrence with parental testing was identified for this variant. Details ▾Hide ▴
Still missing
  • No parental confirmation data were identified
  • No phenotype-matched de novo case report was identified
PS3 No well-established functional study was identified showing a damaging effect of p.(Gly105Arg). Details ▾Hide ▴
Still missing
  • No validated disease-relevant functional assay for this exact variant was identified
PS4 No case-control or affected-individual enrichment data were identified for this variant. Details ▾Hide ▴
Still missing
  • No affected-case counts were identified
  • No enrichment analysis against ancestry-matched controls was identified
PM1 Available evidence does not establish codon 105 as a mutational hotspot or as part of a well-established critical functional domain without benign variation. Details ▾Hide ▴
Still missing
  • No verified hotspot or critical-domain evidence for residue 105 was identified
PM3 No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disease context. Details ▾Hide ▴
Still missing
  • No phase data were identified
  • No recessive case-level evidence was identified
PM5 No evidence was identified that a different missense change at the same codon has been established as pathogenic or likely pathogenic. Details ▾Hide ▴
Still missing
  • No pathogenic same-codon comparator was identified
PM6 No assumed de novo occurrence without full parental confirmation was identified for this variant. Details ▾Hide ▴
Still missing
  • No sporadic or presumed de novo case report was identified
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Still missing
  • No pedigree data were identified
  • No affected or unaffected relative genotypes were identified
PP2 Available evidence does not establish that missense variation in CREB3L3 is a common disease mechanism in a gene with low benign missense variation. Details ▾Hide ▴
Still missing
  • No gene-level missense constraint or mechanism-specific rule was identified
PP4 No phenotype-specific clinical evidence was identified showing a presentation highly specific for a CREB3L3-related disorder in a person carrying this variant. Details ▾Hide ▴
Still missing
  • No case-level phenotype data were identified
PP5 This criterion was not used because external assertions alone are not sufficient evidence without primary supporting data. Details ▾Hide ▴
Sources
PMID:25741868 ↗PMID:28492532 ↗
BS2 Although this variant is observed with homozygotes in population datasets, the available evidence does not establish the disease penetrance and phenotype context needed to apply BS2. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 homozygotes 14
  • gnomAD v4.1 homozygotes 37
Still missing
  • No penetrance framework was identified for applying BS2
  • No phenotype data for population homozygotes were identified
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No well-established functional study was identified showing retained normal function for p.(Gly105Arg). Details ▾Hide ▴
Still missing
  • No validated normal-function assay for this exact variant was identified
BS4 No non-segregation evidence was identified for this variant. Details ▾Hide ▴
Still missing
  • No family-level genotype-phenotype data demonstrating non-segregation were identified
BP1 This is a missense variant, but the available evidence does not establish a gene-specific pattern showing that only truncating variants are typically pathogenic and that missense variation is predominantly benign. Details ▾Hide ▴
Still missing
  • No gene-specific BP1 framework was identified
BP2 No phase data were identified to show this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant. Details ▾Hide ▴
Still missing
  • No phase information was identified
BP5 No evidence was identified for an alternative molecular cause that fully explains the observed phenotype in a person carrying this variant. Details ▾Hide ▴
Still missing
  • No case-level alternate-cause data were identified
BP6 This criterion was not used because external benign assertions alone are not sufficient evidence without primary supporting data. Details ▾Hide ▴
Sources
PMID:25741868 ↗PMID:28492532 ↗
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense change, p.(Gly105Arg), and does not fall into the generic PVS1 null-variant categories such as nonsense, frameshift, or canonical +/-1,2 splice variants. Although loss of function is considered a relevant disease mechanism for CREB3L3, the available PVS1 scaffold does not support applying PVS1 to this variant. Details ▾Hide ▴
Evidence considered
  • CREB3L3 loss-of-function mechanism was considered eligible at the gene level
  • Variant-specific PVS1 scaffold states the change is not in a default null-variant bucket
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
PM4 N/AThis variant is a missense substitution and does not cause a protein length change or in-frame exon-level alteration. Details ▾Hide ▴
Evidence considered
  • Protein consequence p.(Gly105Arg)
BP3 N/AThis variant is not an in-frame deletion or insertion in a repetitive region without known function. Details ▾Hide ▴
Evidence considered
  • Protein consequence p.(Gly105Arg)
BP7 N/AThis variant is a missense substitution rather than a synonymous or intronic change, so BP7 does not apply. Details ▾Hide ▴
Evidence considered
  • Protein consequence p.(Gly105Arg)

Identifiers

Gene
CREB3L3
Transcript
NM_032607.3
Coding (HGVS c.)
NM_032607.3:c.313G>A
Protein (HGVS p.)
NP_115996.1:p.(Gly105Arg)
GRCh38
chr19:4157151 G>A
GRCh37
chr19:4157148 G>A

Gene diagram

Every interpreted variant in CREB3L3, mapped onto the exon structure of NM_032607.3. Select a row to find it on the plot.

CREB3L3NM_032607.3
Fetching transcript structure from UCSC…
gnomAD v4.1 3,478 / 1,613,834 alleles AF 0.00216 · 37 homozygotes · FAF 0.0329
gnomAD v2.1 1,047 / 281,626 alleles AF 0.00372 · 14 homozygotes · FAF 0.0322

By genetic ancestry

gnomAD v4.1

AF 0.0022 · 3478 / 1,613,834 alleles · 37 hom · FAF 0.033
East Asian1540 / 44,844 0.03431 hom
Remaining individuals199 / 62,498 0.00322 hom
Admixed American164 / 59,962 0.00273 hom
European (non-Finnish)1389 / 1,179,984 0.00121 hom
Middle Eastern7 / 6,060 0.0012
African/African American68 / 74,942 0.00091
European (Finnish)49 / 63,966 0.00077
South Asian61 / 91,062 0.00067
Ashkenazi Jewish1 / 29,606 3.4e-05
0 alternate alleles recorded in 1 other group: Amish.

gnomAD v2.1

AF 0.0037 · 1047 / 281,626 alleles · 14 hom · FAF 0.032
East Asian686 / 19,926 0.03413 hom
Remaining individuals25 / 7,212 0.0035
Admixed American117 / 35,432 0.00331 hom
European (non-Finnish)170 / 128,048 0.0013
European (Finnish)17 / 25,110 0.00068
African/African American15 / 24,938 0.0006
South Asian17 / 30,606 0.00056
0 alternate alleles recorded in 1 other group: Ashkenazi Jewish.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.00215512; MAF= 0.21551%, 3478/1613834 alleles, homozygotes = 37) and has highest observed frequency in the East Asian population (AF= 0.0343413; MAF= 3.43413%, 1540/44844 alleles, homozygotes = 31); grpmax FAF= 0.0329142.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.0037177; MAF= 0.37177%, 1047/281626 alleles, homozygotes = 14) and has highest observed frequency in the East Asian population (AF= 0.0344274; MAF= 3.44274%, 686/19926 alleles, homozygotes = 13); grpmax FAF= 0.0321736.

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 SupportingMultiple computational results support a benign interpretation rather than a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, REVEL is 0.257, and BayesDel is -0.423809. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.02
  • REVEL score 0.257
  • BayesDel score -0.423809
Sources
spliceai ↗revelbayesdel
PP3 Available computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, REVEL is 0.257, and BayesDel is -0.423809, which do not provide supportive evidence for pathogenicity. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.02
  • REVEL score 0.257
  • BayesDel score -0.423809
Sources
spliceai ↗revelbayesdel
BP7 N/AThis variant is a missense substitution rather than a synonymous or intronic change, so BP7 does not apply. Details ▾Hide ▴
Evidence considered
  • Protein consequence p.(Gly105Arg)

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.257. BayesDel score = -0.423809.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 3,478 / 1,613,834 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Captured SpliceAI source record Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.00215512; MAF= 0.21551%, 3478/1613834 alleles, homozygotes = 37) and has highest observed frequency in the East Asian population (AF= 0.0343413; MAF= 3.43413%, 1540/44844 alleles, homozygotes = 31); grpmax FAF= 0.0329142.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.0037177; MAF= 0.37177%, 1047/281626 alleles, homozygotes = 14) and has highest observed frequency in the East Asian population (AF= 0.0344274; MAF= 3.44274%, 686/19926 alleles, homozygotes = 13); grpmax FAF= 0.0321736.

ClinVar

This variant has been reported in ClinVar as Benign (2 clinical laboratories).

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.257. BayesDel score = -0.423809.

Somatic

This variant has not previously been reported in somatic cancers (COSMIC).