rs201728850
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The ENST00000613296.6(ALMS1):āc.11953A>Gā(p.Ile3985Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000158 in 1,614,214 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). Synonymous variant affecting the same amino acid position (i.e. I3985I) has been classified as Likely benign.
Frequency
Consequence
ENST00000613296.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALMS1 | NM_001378454.1 | c.11953A>G | p.Ile3985Val | missense_variant | 19/23 | ENST00000613296.6 | NP_001365383.1 | |
ALMS1 | NM_015120.4 | c.11956A>G | p.Ile3986Val | missense_variant | 19/23 | NP_055935.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ALMS1 | ENST00000613296.6 | c.11953A>G | p.Ile3985Val | missense_variant | 19/23 | 1 | NM_001378454.1 | ENSP00000482968 | P3 |
Frequencies
GnomAD3 genomes AF: 0.000145 AC: 22AN: 152210Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000395 AC: 99AN: 250352Hom.: 0 AF XY: 0.000346 AC XY: 47AN XY: 135758
GnomAD4 exome AF: 0.000159 AC: 233AN: 1461886Hom.: 0 Cov.: 74 AF XY: 0.000171 AC XY: 124AN XY: 727246
GnomAD4 genome AF: 0.000144 AC: 22AN: 152328Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11AN XY: 74492
ClinVar
Submissions by phenotype
Alstrom syndrome Uncertain:3Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | May 18, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 02, 2022 | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3986 of the ALMS1 protein (p.Ile3986Val). This variant is present in population databases (rs201728850, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with ALMS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 581362). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 23, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Dec 09, 2021 | The heterozygous c.11953A>G (p.Ile3986Val) missense variant identified in the ALMS1 gene has not been reported in affected individuals in the literature. The variant has 0.0003620 allele frequency in the gnomAD (v2.1.1 and v3.1.2) database (102 out of 281762 heterozygous alleles, no homozygotes). This variant is reported as both a Variant of uncertain significance and likely benign associated with Alstrom syndrome in the ClinVar database (Variation ID: 581362). The variant affects a weakly conserved residue (Ile3986) of ALMS1 protein and is predicted neutral by multiple in silico prediction tools (CADD score = 6.015, REVEL score= 0.243). Based on the available evidence, the heterozygous c.11953A>G (p.Ile3986Val) missense variant identified in the ALMS1 gene is reported as a Variant of Uncertain Significance. - |
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 01, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 04, 2019 | The p.Ile3986Val variant in ALMS1 is classified as likely benign because it has been identified in 0.1% (59/35436) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org), and computational prediction tools predict that this variant does not impact the protein. ACMG/AMP Criteria applied: BS1_Supporting, BP4. - |
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | ALMS1: BP4 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 03, 2024 | In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Retinal dystrophy Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Jan 01, 2022 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 14, 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at