chr2-73572651-A-G
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_001378454.1(ALMS1):āc.10774A>Gā(p.Thr3592Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,614,040 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.10774A>G | p.Thr3592Ala | missense_variant | 16/23 | ENST00000613296.6 | NP_001365383.1 | |
ALMS1 | NM_015120.4 | c.10777A>G | p.Thr3593Ala | missense_variant | 16/23 | NP_055935.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ALMS1 | ENST00000613296.6 | c.10774A>G | p.Thr3592Ala | missense_variant | 16/23 | 1 | NM_001378454.1 | ENSP00000482968 | P3 |
Frequencies
GnomAD3 genomes AF: 0.000559 AC: 85AN: 152170Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000113 AC: 28AN: 248704Hom.: 0 AF XY: 0.0000964 AC XY: 13AN XY: 134914
GnomAD4 exome AF: 0.0000718 AC: 105AN: 1461754Hom.: 0 Cov.: 32 AF XY: 0.0000633 AC XY: 46AN XY: 727162
GnomAD4 genome AF: 0.000558 AC: 85AN: 152286Hom.: 0 Cov.: 32 AF XY: 0.000483 AC XY: 36AN XY: 74458
ClinVar
Submissions by phenotype
Alstrom syndrome Uncertain:2Benign:1
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 01, 2022 | This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 3593 of the ALMS1 protein (p.Thr3593Ala). This variant is present in population databases (rs200467041, 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: 449854). 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 alanine 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 | Mar 18, 2022 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 10, 2023 | Variant summary: ALMS1 c.10771A>G (p.Thr3591Ala) 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 0.00011 in 248704 control chromosomes, predominantly at a frequency of 0.0012 within the African or African-American subpopulation in the gnomAD database. This frequency is only slight lower than expected for a pathogenic variant in ALMS1 causing Alstrom Syndrome (0.0012 vs 0.0014), suggesting this variant may not associate with the disease. To our knowledge, no occurrence of c.10771A>G in individuals affected with Alstrom Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variants have been reported (MYBPC3 c.1505G>A, p.Arg502Gln; TTN c.62134C>T, p.Gln20712X; MYBPC3 c.927-9G>A; internal testing), providing supporting evidence for a benign role. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as likely benign (n=2) or uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 15, 2024 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 25, 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