chr2-73385903-T-TGGAGGAGGAGGA
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP3BP6BS1BS2
The NM_001378454.1(ALMS1):c.63_74dupGGAGGAGGAGGA(p.Glu22_Glu25dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0013 ( 1 hom., cov: 0)
Exomes 𝑓: 0.0025 ( 2 hom. )
Consequence
ALMS1
NM_001378454.1 disruptive_inframe_insertion
NM_001378454.1 disruptive_inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.369
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 -10 ACMG points.
BP3
Nonframeshift variant in repetitive region in NM_001378454.1
BP6
Variant 2-73385903-T-TGGAGGAGGAGGA is Benign according to our data. Variant chr2-73385903-T-TGGAGGAGGAGGA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 412658.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00126 (181/143630) while in subpopulation EAS AF= 0.0236 (108/4582). AF 95% confidence interval is 0.02. There are 1 homozygotes in gnomad4. There are 101 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ALMS1 | NM_001378454.1 | c.63_74dupGGAGGAGGAGGA | p.Glu22_Glu25dup | disruptive_inframe_insertion | Exon 1 of 23 | ENST00000613296.6 | NP_001365383.1 | |
| ALMS1 | NM_015120.4 | c.63_74dupGGAGGAGGAGGA | p.Glu22_Glu25dup | disruptive_inframe_insertion | Exon 1 of 23 | NP_055935.4 |
Ensembl
Frequencies
GnomAD3 genomes 0.00128 AC: 183AN: 143526Hom.: 1 Cov.: 0
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GnomAD4 exome AF: 0.00250 AC: 1392AN: 557702Hom.: 2 Cov.: 0 AF XY: 0.00239 AC XY: 711AN XY: 297806
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GnomAD4 genome 0.00126 AC: 181AN: 143630Hom.: 1 Cov.: 0 AF XY: 0.00145 AC XY: 101AN XY: 69660
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Alstrom syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
not specified Benign:1
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 25, 2019 | Variant summary: The ALMS1 variant, c.66_74dupGGAGGAGGA (p.Glu26_Glu28dup, also known as c.69_77dup) is located in a Glu repetitive region. The variant allele was found at a frequency of 0.0043 in 83366 control chromosomes, predominantly at a frequency of 0.011 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 5-folds over the estimated maximal expected allele frequency for a pathogenic variant in ALMS1 causing Cardiomyopathy phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.66_74dupGGAGGAGGA in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. - |
Cardiovascular phenotype Benign:1
| Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 09, 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. - |
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at