rs777476179
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001378454.1(ALMS1):c.1732del(p.Arg578GlyfsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000583 in 1,613,642 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R578R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001378454.1 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALMS1 | NM_001378454.1 | c.1732del | p.Arg578GlyfsTer17 | frameshift_variant | 8/23 | ENST00000613296.6 | |
ALMS1 | NM_015120.4 | c.1735del | p.Arg579GlyfsTer17 | frameshift_variant | 8/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALMS1 | ENST00000613296.6 | c.1732del | p.Arg578GlyfsTer17 | frameshift_variant | 8/23 | 1 | NM_001378454.1 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151896Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000161 AC: 4AN: 249046Hom.: 0 AF XY: 0.0000296 AC XY: 4AN XY: 135092
GnomAD4 exome AF: 0.0000629 AC: 92AN: 1461746Hom.: 0 Cov.: 54 AF XY: 0.0000633 AC XY: 46AN XY: 727196
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 151896Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74192
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2016 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Alstrom syndrome Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 02, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 21, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 374506). This premature translational stop signal has been observed in individual(s) with Alstrom syndrome (PMID: 24462884). This variant is present in population databases (rs777476179, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Arg579Glyfs*17) 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 10, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jul 10, 2017 | - - |
Leukodystrophy;C1384666:Hearing impairment;C2316810:Stage 5 chronic kidney disease;C3665347:Visual impairment Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | - | - - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 17, 2020 | The c.1735delA variant, located in coding exon 8 of the ALMS1 gene, results from a deletion of one nucleotide at nucleotide position 1735, causing a translational frameshift with a predicted alternate stop codon (p.R579Gfs*17). This variant has been reported in association with Alstrom syndrome in individuals with disease features and a second ALMS1 mutation (Paisey RB et al. Eur J Med Genet, 2014 Feb;57:71-5; Paisey RB et al. J. Clin. Endocrinol. Metab., 2015 Aug;100:E1116-24). 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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at