rs878854998
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001378454.1(ALMS1):c.3016dup(p.Arg1006LysfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,613,688 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000025 ( 0 hom. )
Consequence
ALMS1
NM_001378454.1 frameshift
NM_001378454.1 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -1.55
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 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 2-73449542-T-TA is Pathogenic according to our data. Variant chr2-73449542-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 240992.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALMS1 | NM_001378454.1 | c.3016dup | p.Arg1006LysfsTer15 | frameshift_variant | 8/23 | ENST00000613296.6 | |
ALMS1 | NM_015120.4 | c.3019dup | p.Arg1007LysfsTer15 | frameshift_variant | 8/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALMS1 | ENST00000613296.6 | c.3016dup | p.Arg1006LysfsTer15 | frameshift_variant | 8/23 | 1 | NM_001378454.1 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152010Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000241 AC: 6AN: 248472Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 134788
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GnomAD4 exome AF: 0.0000246 AC: 36AN: 1461678Hom.: 0 Cov.: 39 AF XY: 0.0000261 AC XY: 19AN XY: 727152
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GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152010Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74242
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Alstrom syndrome Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 23, 2023 | This sequence change creates a premature translational stop signal (p.Arg1007Lysfs*15) 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 (rs751695119, gnomAD 0.007%). 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: 240992). For these reasons, this variant has been classified as Pathogenic. - |
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