rs1476205467
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_001378454.1(ALMS1):c.11615_11616del(p.Ser3872TyrfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
ALMS1
NM_001378454.1 frameshift
NM_001378454.1 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.959
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 16 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 2-73599465-ACT-A is Pathogenic according to our data. Variant chr2-73599465-ACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 553694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-73599465-ACT-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALMS1 | NM_001378454.1 | c.11615_11616del | p.Ser3872TyrfsTer19 | frameshift_variant | 17/23 | ENST00000613296.6 | |
ALMS1 | NM_015120.4 | c.11618_11619del | p.Ser3873TyrfsTer19 | frameshift_variant | 17/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALMS1 | ENST00000613296.6 | c.11615_11616del | p.Ser3872TyrfsTer19 | frameshift_variant | 17/23 | 1 | NM_001378454.1 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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GnomAD3 exomes AF: 0.00000402 AC: 1AN: 249012Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135092
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000684 AC: 10AN: 1461322Hom.: 0 AF XY: 0.00000550 AC XY: 4AN XY: 726996
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Data not reliable, filtered out with message: AS_VQSR
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Alstrom syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Sep 12, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 21, 2023 | This sequence change creates a premature translational stop signal (p.Ser3873Tyrfs*19) 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 present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with ALMS1-related conditions (PMID: 26111748, 26969326, 29588463). ClinVar contains an entry for this variant (Variation ID: 553694). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Dec 04, 2018 | - - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 23, 2021 | The c.11618_11619delCT pathogenic mutation, located in coding exon 17 of the ALMS1 gene, results from a deletion of two nucleotides at nucleotide positions 11618 to 11619, causing a translational frameshift with a predicted alternate stop codon (p.S3873Yfs*19). This mutation has been detected with other mutations in the ALMS1 gene in several individuals with Alstrom syndrome (Nadol JB et al. Audiol Neurootol, 2015 Jun;20:267-72; Citton V et al. J Neuroradiol, 2016 Jun;43:195-9; Sloan-Heggen CM et al. Hum Genet, 2016 Apr;135:441-450; Sanchez-Navarro I et al. Sci Rep, 2018 03;8:5285; Bea-Mascato B et al. Genes (Basel), 2021 02;12). 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