rs201971114
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The NM_001378454.1(ALMS1):āc.4316A>Cā(p.Tyr1439Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000743 in 1,614,084 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1439C) has been classified as Uncertain significance.
Frequency
Consequence
NM_001378454.1 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 | UniProt |
---|---|---|---|---|---|---|---|
ALMS1 | NM_001378454.1 | c.4316A>C | p.Tyr1439Ser | missense_variant | 8/23 | ENST00000613296.6 | |
ALMS1 | NM_015120.4 | c.4319A>C | p.Tyr1440Ser | missense_variant | 8/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALMS1 | ENST00000613296.6 | c.4316A>C | p.Tyr1439Ser | missense_variant | 8/23 | 1 | NM_001378454.1 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.000342 AC: 52AN: 152134Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000763 AC: 19AN: 249154Hom.: 0 AF XY: 0.0000518 AC XY: 7AN XY: 135172
GnomAD4 exome AF: 0.0000465 AC: 68AN: 1461832Hom.: 0 Cov.: 39 AF XY: 0.0000303 AC XY: 22AN XY: 727216
GnomAD4 genome ? AF: 0.000342 AC: 52AN: 152252Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26AN XY: 74460
ClinVar
Submissions by phenotype
Alstrom syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Jan 14, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 2022 | This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 1440 of the ALMS1 protein (p.Tyr1440Ser). This variant is present in population databases (rs201971114, gnomAD 0.1%). 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: 459868). 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 serine 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 | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | Potent mutations in ALMS1 are associated with a rare condition called Alstrom syndrome. It can cause excessive eating, insulin resistance. However, no evidence is found to ascertain the role of rs201971114 in Alstrom syndrome yet. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 19, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 27, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Monogenic diabetes Benign:1
Likely benign, criteria provided, single submitter | research | Personalized Diabetes Medicine Program, University of Maryland School of Medicine | Jun 01, 2018 | ACMG criteria: BP4 (8 predictors plus Revel score: 0.01), BP1 (missense in gene with truncating known)= likely benign - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 16, 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