NM_004168.4:c.840C>T

SDHA · NP_004159.2:p.(Ile280=) · NM_004168.4

GRCh37: chr5:231060 C>T · GRCh38: chr5:230945 C>T

Gene: SDHA Transcript: NM_004168.4

Final call

VUS

PM2 BP7

Variant details

Gene

SDHA

Transcript

NM_004168.4

Protein

NP_004159.2:p.(Ile280=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: The combination of PM2 and BP7 does not satisfy ACMG/AMP 2015 criteria for pathogenic, likely pathogenic, likely benign, or benign classification; therefore this variant is classified as of uncertain significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This is a synonymous SDHA variant, NM_004168.4:c.840C>T (p.Ile280=), and it is not a predicted loss-of-function variant.	prefetch_json
PS1	N/A	PS1 is not applicable because this synonymous change does not alter the amino acid sequence.	prefetch_json
PS2	Not assessed	No de novo data with confirmed maternity and paternity were identified for this variant.
PS3	Not assessed	No well-established functional studies demonstrating a damaging effect of this variant on SDHA function were identified.	literature_pass_json
PS4	Not met	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.	literature_pass_json PMID:24893135 PMID:25394175 PMID:28492532
PM1	Not met	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.	hotspots
PM2	Met	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.	gnomad_v2 gnomad_v4
PM3	Not assessed	No data were identified showing this variant in trans with a pathogenic variant in a recessive disorder context.
PM4	N/A	PM4 is not applicable because this variant does not change protein length and is not an in-frame insertion or deletion.	prefetch_json
PM5	N/A	PM5 is not applicable because this synonymous change does not create a novel missense substitution at residue 280.	prefetch_json
PM6	Not assessed	No assumed de novo occurrence without confirmed parentage was identified for this variant.
PP1	Not assessed	No segregation data were identified to show that this variant tracks with disease in affected family members.
PP2	N/A	PP2 is not applicable because this variant is synonymous rather than missense.	prefetch_json
PP3	Not met	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.	spliceai
PP4	Not assessed	No phenotype or family history data were identified to show a clinical presentation highly specific for an SDHA-related disorder attributable to this variant.
PP5	Not assessed	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.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	Not assessed	No data were identified showing this variant in healthy adult individuals in a context sufficient to support BS2.
BS3	Not assessed	No well-established functional studies demonstrating no damaging effect of this variant were identified.	literature_pass_json
BS4	Not assessed	No family data were identified showing lack of segregation of this variant with disease.
BP1	N/A	BP1 is not applicable because this variant is synonymous rather than a missense change.	prefetch_json
BP2	Not assessed	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.
BP3	N/A	BP3 is not applicable because this variant is not an in-frame insertion or deletion in a repetitive region.
BP4	N/A	BP4 was not separately applied because the available in silico evidence relates to a synonymous variant and is more specifically captured under BP7.	spliceai
BP5	Not assessed	No alternate molecular explanation for the phenotype was identified that would support BP5.
BP6	Not assessed	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.	clinvar
BP7	Met	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.	prefetch_json spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.