rs1370417967
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001378454.1(ALMS1):βc.7373_7376delβ(p.Asp2458AlafsTer18) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000496 in 1,613,914 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 32)
Exomes π: 0.0000048 ( 0 hom. )
Consequence
ALMS1
NM_001378454.1 frameshift
NM_001378454.1 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.18
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 Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
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Variant 2-73453897-CAGAT-C is Pathogenic according to our data. Variant chr2-73453897-CAGAT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 556391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALMS1 | NM_001378454.1 | c.7373_7376del | p.Asp2458AlafsTer18 | frameshift_variant | 8/23 | ENST00000613296.6 | |
ALMS1 | NM_015120.4 | c.7376_7379del | p.Asp2459AlafsTer18 | frameshift_variant | 8/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALMS1 | ENST00000613296.6 | c.7373_7376del | p.Asp2458AlafsTer18 | frameshift_variant | 8/23 | 1 | NM_001378454.1 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152096Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461818Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 727198
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152096Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74284
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Alstrom syndrome Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 26, 2018 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 02, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 29, 2023 | This sequence change creates a premature translational stop signal (p.Asp2459Alafs*18) in the ALMS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALMS1 are known to be pathogenic (PMID: 17594715). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Alstrom syndrome (PMID: 25846608). ClinVar contains an entry for this variant (Variation ID: 556391). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 07, 2023 | The c.7376_7379delATAG pathogenic mutation, located in coding exon 8 of the ALMS1 gene, results from a deletion of 4 nucleotides at nucleotide positions 7376 to 7379, causing a translational frameshift with a predicted alternate stop codon (p.D2459Afs*18). In a cohort of individuals with Alstrom syndrome, this mutation was identified in 2 alleles (Marshall JD et al. Hum. Mutat., 2015 Jul;36:660-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at