rs142558799
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The NM_001378454.1(ALMS1):c.10892G>A(p.Arg3631His) variant causes a missense change. The variant allele was found at a frequency of 0.000159 in 1,614,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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 Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000611 AC: 93AN: 152124Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000241 AC: 60AN: 249204Hom.: 0 AF XY: 0.000237 AC XY: 32AN XY: 135172
GnomAD4 exome AF: 0.000112 AC: 164AN: 1461816Hom.: 0 Cov.: 32 AF XY: 0.000109 AC XY: 79AN XY: 727202
GnomAD4 genome AF: 0.000611 AC: 93AN: 152242Hom.: 0 Cov.: 32 AF XY: 0.000658 AC XY: 49AN XY: 74434
ClinVar
Submissions by phenotype
not specified Uncertain:3
Variant classified as Uncertain Significance - Favor Benign. The p.Arg3632His va riant in ALMS1 gene has not been previously reported in individuals with hearing loss or Alstrom syndrome, but has been identified in several populations by the Genome Aggregation Database with the highest frequency of 0.21%(51/24014) of Af rican chromosomes (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs142558799). This variant has also been reported in an affected individual of unspecified ph enotypes in ClinVar (Variation ID: 390222). Computational prediction tools and c onservation analysis do not provide strong support for or against an impact to t he protein. In summary, while the clinical significance of the p.Arg3630His vari ant is uncertain, the frequency data indicate that it is more likely to be benig n. ACMG/AMP criteria applied: BS1_supporting. -
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Variant summary: ALMS1 c.10889G>A (p.Arg3630His, alternative name c.10895G>A) 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 0.00028 in 276814 control chromosomes. This frequency is not higher than expected for a pathogenic variant in ALMS1 causing Cardiomyopathy (0.00028 vs 0.0022), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.10889G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided Uncertain:3
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Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -
Alstrom syndrome Uncertain:1Benign:2
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ALMS1 NM_015120.4 exon 16 p.Arg3630His (c.10889G>A): This variant has not been reported in the literature and is present in 0.2% (51/24014) of African alleles in the Genome Aggregation Database (http://gnomad-old.broadinstitute.org/variant/2-73799896-G-A). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. However, the variant amino acid Histidine (His) is present in two species (dolphin, killer whale). In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Cardiovascular phenotype Benign:1
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