rs140670994
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_001378454.1(ALMS1):c.3732G>A(p.Lys1244=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000257 in 1,614,024 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0013 ( 1 hom., cov: 33)
Exomes 𝑓: 0.00015 ( 2 hom. )
Consequence
ALMS1
NM_001378454.1 synonymous
NM_001378454.1 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.948
Genes affected
ALMS1 (HGNC:428): (ALMS1 centrosome and basal body associated protein) This gene encodes a protein containing a large tandem-repeat domain as well as additional low complexity regions. The encoded protein functions in microtubule organization, particularly in the formation and maintanance of cilia. Mutations in this gene cause Alstrom syndrome. There is a pseudogene for this gene located adjacent in the same region of chromosome 2. Alternative splice variants have been described but their full length nature has not been determined. [provided by RefSeq, Apr 2014]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BP6
?
Variant 2-73450259-G-A is Benign according to our data. Variant chr2-73450259-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 198872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
Synonymous conserved (PhyloP=-0.948 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00128 (195/152222) while in subpopulation AFR AF= 0.00431 (179/41530). AF 95% confidence interval is 0.00379. There are 1 homozygotes in gnomad4. There are 107 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAdExome4 at 2 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALMS1 | NM_001378454.1 | c.3732G>A | p.Lys1244= | synonymous_variant | 8/23 | ENST00000613296.6 | |
ALMS1 | NM_015120.4 | c.3735G>A | p.Lys1245= | synonymous_variant | 8/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALMS1 | ENST00000613296.6 | c.3732G>A | p.Lys1244= | synonymous_variant | 8/23 | 1 | NM_001378454.1 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00127 AC: 193AN: 152104Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.000350 AC: 87AN: 248914Hom.: 0 AF XY: 0.000296 AC XY: 40AN XY: 134984
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GnomAD4 exome AF: 0.000150 AC: 220AN: 1461802Hom.: 2 Cov.: 39 AF XY: 0.000138 AC XY: 100AN XY: 727196
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GnomAD4 genome ? AF: 0.00128 AC: 195AN: 152222Hom.: 1 Cov.: 33 AF XY: 0.00144 AC XY: 107AN XY: 74428
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 28, 2016 | Variant summary: The c.3729G>A (alternative name c.3735G>A) in ALMS1 gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect a normal splicing, however no functional studies supporting these predictions were published at the time of evaluation. The variant is present in the large control population dataset of ExAC at a frequency 0.0004 (48/120640 chrs tested), predominantly in individuals of African origin (0.0045; 44/9792 chrs tested). This frequency exceeds the estimated maximal expected allele frequency of a pathogenic variant in ALMS1 gene (0.0022). The variant is present in a control population dataset of gmomAD predominantly in individuals of African origin: 0.0045 (117/ 25854 chrs); however, since the data set is still in beta mode, this data was not captured in pbGP. The c. 3729G>A has not, to our knowledge, been reported in affected individuals via published reports, but is cited as Likely Benign by a reputable database/clinical laboratory. The variant seems to be an ethnic specific polymorphism, therefore it has been classified as Benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 05, 2015 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 29, 2021 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 01, 2019 | 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. - |
Alstrom syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at