rs144599870
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1
The NM_004168.4(SDHA):āc.136A>Gā(p.Lys46Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00025 in 1,613,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_004168.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SDHA | NM_004168.4 | c.136A>G | p.Lys46Glu | missense_variant | Exon 2 of 15 | ENST00000264932.11 | NP_004159.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SDHA | ENST00000264932.11 | c.136A>G | p.Lys46Glu | missense_variant | Exon 2 of 15 | 1 | NM_004168.4 | ENSP00000264932.6 | ||
ENSG00000286001 | ENST00000651543.1 | n.136A>G | non_coding_transcript_exon_variant | Exon 2 of 24 | ENSP00000499215.1 |
Frequencies
GnomAD3 genomes AF: 0.00132 AC: 201AN: 152226Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000287 AC: 72AN: 251180Hom.: 0 AF XY: 0.000169 AC XY: 23AN XY: 135744
GnomAD4 exome AF: 0.000138 AC: 202AN: 1460838Hom.: 0 Cov.: 30 AF XY: 0.000107 AC XY: 78AN XY: 726836
GnomAD4 genome AF: 0.00133 AC: 202AN: 152344Hom.: 0 Cov.: 33 AF XY: 0.00133 AC XY: 99AN XY: 74500
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:2
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Variant summary: SDHA c.136A>G (p.Lys46Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 1613182 control chromosomes, predominantly at a frequency of 0.0049 within the African or African-American subpopulation in the gnomAD database. This suggests that the variant is very likely a benign polymorphism found primarily in populations of African or African-American origin. c.136A>G has been reported in the literature in at-least one individual affected with abdominal a paraganglioma (example: Casey_2017). This report does not provide unequivocal conclusions about association of the variant with Neurodegeneration With Ataxia And Late-Onset Optic Atrophy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28546994). ClinVar contains an entry for this variant (Variation ID: 224951). Based on the evidence outlined above, the variant was classified as likely benign. -
Paragangliomas 5 Uncertain:2
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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Hereditary cancer-predisposing syndrome Benign:2
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. -
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Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Benign:1
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not provided Benign:1
This variant is associated with the following publications: (PMID: 23666964, 28546994, 26802149) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at