rs398122992
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001378454.1(ALMS1):βc.11113_11131delβ(p.Arg3705LeufsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. R3705R) has been classified as Uncertain significance. 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.11113_11131del | p.Arg3705LeufsTer11 | frameshift_variant | 16/23 | ENST00000613296.6 | |
ALMS1 | NM_015120.4 | c.11116_11134del | p.Arg3706LeufsTer11 | frameshift_variant | 16/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALMS1 | ENST00000613296.6 | c.11113_11131del | p.Arg3705LeufsTer11 | frameshift_variant | 16/23 | 1 | NM_001378454.1 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152158Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000161 AC: 4AN: 248926Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135218
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461810Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727208
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152158Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74322
ClinVar
Submissions by phenotype
Alstrom syndrome Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 29, 2021 | - - |
Pathogenic, criteria provided, single submitter | research | Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change creates a premature translational stop signal (p.Arg3706Leufs*11) 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 (rs398122992, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with Alstrom syndrome (PMID: 24595103, 26047050). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as c.11110_11128del (p.R3704LfsX11). ClinVar contains an entry for this variant (Variation ID: 92191). For these reasons, this variant has been classified as Pathogenic. - |
not provided Other:1
not provided, no classification provided | literature only | Johns Hopkins Genetic Resources Core Facility; Johns Hopkins University | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at