rs201154998
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_001378454.1(ALMS1):c.2536G>A(p.Gly846Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,613,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 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_001378454.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALMS1 | NM_001378454.1 | c.2536G>A | p.Gly846Arg | missense_variant | 8/23 | ENST00000613296.6 | NP_001365383.1 | |
ALMS1 | NM_015120.4 | c.2536G>A | p.Gly846Arg | missense_variant | 8/23 | NP_055935.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ALMS1 | ENST00000613296.6 | c.2536G>A | p.Gly846Arg | missense_variant | 8/23 | 1 | NM_001378454.1 | ENSP00000482968.1 |
Frequencies
GnomAD3 genomes AF: 0.000204 AC: 31AN: 152002Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000723 AC: 18AN: 248836Hom.: 0 AF XY: 0.0000519 AC XY: 7AN XY: 134962
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461782Hom.: 0 Cov.: 40 AF XY: 0.0000138 AC XY: 10AN XY: 727190
GnomAD4 genome AF: 0.000204 AC: 31AN: 152120Hom.: 0 Cov.: 33 AF XY: 0.000229 AC XY: 17AN XY: 74372
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 27, 2022 | Variant summary: ALMS1 c.2533G>A/p.Gly845Arg (also known as c.2539G>A/p.G847R in RefSeq) results in a non-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 7.2e-05 in 248836 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ALMS1 causing Cardiomyopathy (7.2e-05 vs 0.0022), allowing no conclusion about variant significance. c.2533G>A has been reported in the literature in individuals affected with congenital heart disease or inherited retinal and optical nerve disorders. These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS n=2, likely benign n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 29, 2024 | Identified in cohort of patients with syndromic or non-syndromic inherited retinal dystrophies (IRDs) (PMID: 32483926); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32483926) - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 09, 2019 | 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. - |
Alstrom syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at