SDHAc.840C>TUncertain significance

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Variant interpretation report

SDHA c.840C>T, p.(Ile280=)

NM_004168.4:c.840C>T NP_004159.2:p.(Ile280=) View identifiers

Classification

Uncertain significance

Variant description:

No variant summary was recorded for this case.

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

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About SDHA

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 strength unspecified (benign) · 1 strength unspecified (pathogenic)
Expert rules: Not recorded

Evidence considered

View criteria

Applied evidence criteria

PM2: This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which is below the default PM2 rarity threshold of 0.1% for generic ACMG population assessment.
BP7: This is a synonymous variant, p.(Ile280=), and SpliceAI predicts no significant splice impact with a maximum delta score of 0.04, supporting no expected effect on RNA splicing or protein sequence.

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: 1 Benign evidence criteria: 1

Pathogenic criteria applied · 1

PM2Met

PM2

This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which is below the default PM2 rarity threshold of 0.1% for generic ACMG population assessment.

Benign criteria applied · 1

BP7Met

BP7

This is a synonymous variant, p.(Ile280=), and SpliceAI predicts no significant splice impact with a maximum delta score of 0.04, supporting no expected effect on RNA splicing or protein sequence.

Recorded classification: Uncertain significance

Generic ACMG/AMP 2015 final-classification combination rules were used as the applicable fallback framework because no official or custom gene-specific final-classification framework was available.

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

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

Absent from gnomAD v2.1.

Applied · PM2 →

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 · BP7 →

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

Not assessed

No COSMIC evidence statement is recorded in this case.

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only Cancer Hotspots ↗

For specialists

Technical detail

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

28 criteria with recorded statuses: 2 met · 5 not met · 13 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

The SDHA c.840C>T (p.Ile280=) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as Likely benign with criteria provided from a single submitter.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the default PM2 rarity threshold of 0.1% and does not reach the BS1 (>0.3%) or BA1 (>1%) benign frequency thresholds.

In silico assessment is consistent with a benign synonymous effect, as the variant does not change the amino acid sequence and SpliceAI predicts no significant splice impact with a maximum delta score of 0.04.

Met · 2

PM2 MetThis variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which is below the default PM2 rarity threshold of 0.1% for generic ACMG population assessment. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: absent
gnomAD v4.1: absent

Sources

gnomad_v2 ↗gnomad_v4 ↗

BP7 MetThis is a synonymous variant, p.(Ile280=), and SpliceAI predicts no significant splice impact with a maximum delta score of 0.04, supporting no expected effect on RNA splicing or protein sequence. Details ▾Hide ▴

Evidence considered

Protein consequence is NP_004159.2:p.(Ile280=)
SpliceAI max delta score = 0.04

Sources

prefetch_jsonspliceai ↗

Not met · 5 · evaluated, threshold not reached

PS4 Available evidence does not show that this variant is enriched in affected individuals compared with controls. The screened literature did not provide variant-specific case-control or prevalence data supporting increased disease frequency. Details ▾Hide ▴

Evidence considered

PS4 screen reviewed 3 publications and none passed
No variant-specific enrichment data identified

Still missing

Variant-specific case enrichment or case-control data

Sources

literature_pass_jsonPMID:24893135 ↗PMID:25394175 ↗PMID:28492532 ↗248931352539417528492532

PM1 This variant has not been identified in a mutational hotspot or other well-established critical functional domain without benign variation. Cancer Hotspots did not show a statistically significant hotspot at this residue. Details ▾Hide ▴

Evidence considered

Cancer Hotspots: no hotspot row found for SDHA I280

Sources

hotspots ↗

PP3 Available computational evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.04, which is below commonly used splice concern thresholds. Details ▾Hide ▴

Evidence considered

SpliceAI max delta score = 0.04

Sources

spliceai ↗

BA1 This variant does not meet BA1 because it is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not exceed the 1% benign stand-alone frequency threshold. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: absent
gnomAD v4.1: absent

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 This variant does not meet BS1 because it is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not exceed the default 0.3% benign strong frequency threshold. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: absent
gnomAD v4.1: absent

Sources

gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 13 · no assessment recorded

PS2 No de novo data with confirmed maternity and paternity were identified for this variant. Details ▾Hide ▴

Still missing

Variant-specific parental testing data

PS3 No well-established functional studies demonstrating a damaging effect of this variant on SDHA function were identified. Details ▾Hide ▴

Evidence considered

Literature triage did not identify functional evidence for PS3

Still missing

Validated variant-specific functional assay data

Sources

literature_pass_json

PM3 No data were identified showing this variant in trans with a pathogenic variant in a recessive disorder context. Details ▾Hide ▴

Still missing

Phase data and genotype information in affected individuals

PM6 No assumed de novo occurrence without confirmed parentage was identified for this variant. Details ▾Hide ▴

Still missing

Variant-specific de novo reports

PP1 No segregation data were identified to show that this variant tracks with disease in affected family members. Details ▾Hide ▴

Still missing

Pedigree-based segregation data

PP4 No phenotype or family history data were identified to show a clinical presentation highly specific for an SDHA-related disorder attributable to this variant. Details ▾Hide ▴

Still missing

Detailed phenotype, tumor profile, and family history

PP5 ClinVar lists this variant as Likely benign with criteria provided from a single submitter rather than as a pathogenic assertion from an expert panel or other established authoritative source, so PP5 is not applied. Details ▾Hide ▴

Evidence considered

ClinVar classification: Likely benign; review status: criteria provided, single submitter

Sources

clinvar ↗28492532

BS2 No data were identified showing this variant in healthy adult individuals in a context sufficient to support BS2. Details ▾Hide ▴

Still missing

Well-documented observations in unaffected individuals

BS3 No well-established functional studies demonstrating no damaging effect of this variant were identified. Details ▾Hide ▴

Evidence considered

No benign functional assay evidence identified

Still missing

Validated benign functional assay data

Sources

literature_pass_json

BS4 No family data were identified showing lack of segregation of this variant with disease. Details ▾Hide ▴

Still missing

Non-segregation data in informative families

BP2 No phase data were identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant in a way that would support BP2. Details ▾Hide ▴

Still missing

Phase information with other clinically relevant variants

BP5 No alternate molecular explanation for the phenotype was identified that would support BP5. Details ▾Hide ▴

Still missing

Comprehensive phenotype and alternate-cause evaluation

BP6 ClinVar lists this variant as Likely benign, but the available assertion is from a single submitter rather than an expert panel or other established authoritative benign source, so BP6 is not applied. Details ▾Hide ▴

Evidence considered

ClinVar classification: Likely benign; review status: criteria provided, single submitter

Sources

clinvar ↗28492532

Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AThis is a synonymous SDHA variant, NM_004168.4:c.840C>T (p.Ile280=), and it is not a predicted loss-of-function variant. Details ▾Hide ▴

Evidence considered

NM_004168.4:c.840C>T corresponds to NP_004159.2:p.(Ile280=)

Sources

prefetch_json

PS1 N/APS1 is not applicable because this synonymous change does not alter the amino acid sequence. Details ▾Hide ▴

Evidence considered

Protein consequence is NP_004159.2:p.(Ile280=)

Sources

prefetch_json

PM4 N/APM4 is not applicable because this variant does not change protein length and is not an in-frame insertion or deletion. Details ▾Hide ▴

Evidence considered

Protein consequence is synonymous

Sources

prefetch_json

PM5 N/APM5 is not applicable because this synonymous change does not create a novel missense substitution at residue 280. Details ▾Hide ▴

Evidence considered

Protein consequence is NP_004159.2:p.(Ile280=)

Sources

prefetch_json

PP2 N/APP2 is not applicable because this variant is synonymous rather than missense. Details ▾Hide ▴

Evidence considered

Protein consequence is synonymous

Sources

prefetch_json

BP1 N/ABP1 is not applicable because this variant is synonymous rather than a missense change. Details ▾Hide ▴

Evidence considered

Protein consequence is synonymous

Sources

prefetch_json

BP3 N/ABP3 is not applicable because this variant is not an in-frame insertion or deletion in a repetitive region. Details ▾Hide ▴

No further detail was recorded.

BP4 N/ABP4 was not separately applied because the available in silico evidence relates to a synonymous variant and is more specifically captured under BP7. Details ▾Hide ▴

Evidence considered

SpliceAI max delta score = 0.04

Sources

spliceai ↗

Identifiers

Gene: SDHA
Transcript: NM_004168.4
Coding (HGVS c.): NM_004168.4:c.840C>T
Protein (HGVS p.): NP_004159.2:p.(Ile280=)
GRCh38: chr5:230945 C>T
GRCh37: chr5:231060 C>T

Gene diagram

Every interpreted variant in SDHA, mapped onto the exon structure of NM_004168.4. Select a row to find it on the plot.

SDHANM_004168.4

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in SDHA — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 Allele count data not recorded

gnomAD v2.1 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

Protein consequence is NP_004159.2:p.(Ile280=)
SpliceAI max delta score = 0.04

Sources

prefetch_jsonspliceai ↗

Evidence considered

SpliceAI max delta score = 0.04

Sources

spliceai ↗

BP4 N/ABP4 was not separately applied because the available in silico evidence relates to a synonymous variant and is more specifically captured under BP7. Details ▾Hide ▴

Evidence considered

SpliceAI max delta score = 0.04

Sources

spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).

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 Captured gnomAD v4.1 source record 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

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB 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

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

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

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).

Functional

OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.