rs201252375
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_001378454.1(ALMS1):c.9712C>T(p.Arg3238Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000415 in 1,613,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. 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. R3238H) has been classified as Uncertain significance.
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 | UniProt |
---|---|---|---|---|---|---|---|
ALMS1 | NM_001378454.1 | c.9712C>T | p.Arg3238Cys | missense_variant | 11/23 | ENST00000613296.6 | |
ALMS1 | NM_015120.4 | c.9715C>T | p.Arg3239Cys | missense_variant | 11/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALMS1 | ENST00000613296.6 | c.9712C>T | p.Arg3238Cys | missense_variant | 11/23 | 1 | NM_001378454.1 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.000500 AC: 76AN: 152148Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000589 AC: 147AN: 249464Hom.: 0 AF XY: 0.000569 AC XY: 77AN XY: 135344
GnomAD4 exome AF: 0.000406 AC: 593AN: 1461778Hom.: 0 Cov.: 32 AF XY: 0.000432 AC XY: 314AN XY: 727188
GnomAD4 genome ? AF: 0.000500 AC: 76AN: 152148Hom.: 0 Cov.: 32 AF XY: 0.000444 AC XY: 33AN XY: 74332
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | ALMS1: BP4 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 08, 2020 | - - |
Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | May 02, 2017 | p.Arg3239Cys (c.9715C>T) in exon 11 of the ALMS1 gene (NM_015120.4) Chromosome position: 2:73747074 C / T Based on the information reviewed below, including this variant’s relatively high frequency in the Ashkenazi Jewish population (MAF=0.73%), coupled with poor conservation at this residue across evolution (several species have Cysteine as the default amino acid), we classify it as a Variant of Uncertain Significance, Probably Benign, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. The ALMS1 gene is associated with autosomal recessive Alstrom syndrome (MedGen UID: 78675). For this reason, any one heterozygous variant is an unlikely explanation for disease, although it cannot be ruled out. This variant has not been reported in the literature in association with disease. It has been reported to ClinVar only by Invitae as of 4/29/2017. This is a non-conservative amino acid change, resulting in the replacement of a positively-charged Arginine with a polar Cysteine that it capable of forming disulfide bridges. Arginine at this location is very poorly conserved across vertebrate species. In fact, Cysteine is the default amino acid in at least 3 species. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). There are no Likely Pathogenic or Pathogenic variants listed within 10 amino acids of this residue in ClinVar as of 4/29/2017. Most Pathogenic variants in ALMS1 listed in ClinVar are truncating (frameshift or nonsense) and not missense like this one. This particular transcript for ALMS1 is not found in gnomAD. However, there is an Arg3237Cys variant in gnomAD (rs201252375) that appears to be the same thing. It has been reported in 170 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Overall MAF: 0.06%. Specifically, the variant was observed in 74/5,075 Ashkenazi Jews (for the highest allele frequency: 0.73%), 81/63,302 non-Finnish Europeans, 6 Finnish Europeans, 6 Other, 2 Latinos, and 1 South Asian. Our patient’s ancestry is from Belarus and Ukraine. The phenotype of the individuals in gnomAD is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. - |
Alstrom syndrome Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 05, 2020 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 09, 2020 | Variant summary: ALMS1 c.9709C>T (p.Arg3237Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00059 in 249464 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ALMS1 causing Alstrom Syndrome (0.00059 vs 0.0014), allowing no conclusion about variant significance. c.9709C>T has been reported in the literature in individuals affected with Alstrom Syndrome or Very Early Onset Atrial Fibrillation (Zmyslowska_2016, Goodyer_2019). These reports do not provide unequivocal conclusions about association of the variant with Alstrom Syndrome. 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. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 06, 2021 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at