2-73448365-G-A
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_001378454.1(ALMS1):c.1838G>A(p.Gly613Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000394 in 1,613,924 control chromosomes in the GnomAD database, including 5 homozygotes. 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 Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00199 AC: 303AN: 152020Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000421 AC: 105AN: 249178Hom.: 1 AF XY: 0.000296 AC XY: 40AN XY: 135178
GnomAD4 exome AF: 0.000228 AC: 334AN: 1461786Hom.: 4 Cov.: 53 AF XY: 0.000190 AC XY: 138AN XY: 727194
GnomAD4 genome AF: 0.00199 AC: 302AN: 152138Hom.: 1 Cov.: 32 AF XY: 0.00212 AC XY: 158AN XY: 74378
ClinVar
Submissions by phenotype
Alstrom syndrome Uncertain:1Benign:2
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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 rs148040591 in Alstrom syndrome yet. -
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not specified Benign:3
p.Gly612Asp in exon 8 of ALMS1: This variant is not expected to have clinical si gnificance because it has been identified in 0.64% (63/9800) of African chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs148040591). -
Variant summary: ALMS1 c.1835G>A (p.Gly612Asp), also referred to as c.1841G>A (p.Gly614Asp) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00042 in 249178 control chromosomes, predominantly at a frequency of 0.0065 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in ALMS1 causing Alstrom Syndrome With Dilated Cardiomyopathy phenotype (0.0018), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.1835G>A in individuals affected with Alstrom Syndrome With Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Sevenclinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=6; VUS, n=1). Based on the evidence outlined above, the variant was classified as likely benign. -
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not provided Uncertain:1Benign:1
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Monogenic diabetes Benign:1
ACMG criteria: PP3 (2 predictors), BP4 (7 predictors), BP1 (missense in gene with truncating cause disease), Emory calls VUS, cases and controls similar frequency=likely benign -
Cardiovascular phenotype Benign:1
This alteration is classified as 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