rs376391115
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM5BP4_ModerateBP6BS1
The NM_004168.4(SDHA):c.1661G>A(p.Arg554Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,611,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R554W) has been classified as Pathogenic.
Frequency
Consequence
NM_004168.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SDHA | NM_004168.4 | c.1661G>A | p.Arg554Gln | missense_variant, splice_region_variant | Exon 12 of 15 | ENST00000264932.11 | NP_004159.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SDHA | ENST00000264932.11 | c.1661G>A | p.Arg554Gln | missense_variant, splice_region_variant | Exon 12 of 15 | 1 | NM_004168.4 | ENSP00000264932.6 | ||
ENSG00000286001 | ENST00000651543.1 | n.*394G>A | splice_region_variant, non_coding_transcript_exon_variant | Exon 11 of 24 | ENSP00000499215.1 | |||||
ENSG00000286001 | ENST00000651543.1 | n.*394G>A | 3_prime_UTR_variant | Exon 11 of 24 | ENSP00000499215.1 |
Frequencies
GnomAD3 genomes AF: 0.0000854 AC: 13AN: 152196Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000279 AC: 70AN: 251128Hom.: 1 AF XY: 0.000258 AC XY: 35AN XY: 135712
GnomAD4 exome AF: 0.0000528 AC: 77AN: 1459158Hom.: 0 Cov.: 30 AF XY: 0.0000551 AC XY: 40AN XY: 725956
GnomAD4 genome AF: 0.0000854 AC: 13AN: 152314Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8AN XY: 74486
ClinVar
Submissions by phenotype
Paragangliomas 5 Uncertain:2Benign:1
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This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
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not specified Uncertain:1
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Mitochondrial complex II deficiency, nuclear type 1 Uncertain:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Leigh syndrome Uncertain:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
not provided Uncertain:1
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with lung adenocarcinoma (Tian et al., 2020); This variant is associated with the following publications: (PMID: 31721094) -
Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Benign:1
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Hereditary cancer-predisposing syndrome Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
SDHA-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Hereditary pheochromocytoma-paraganglioma Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at