rs779366889
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001378454.1(ALMS1):βc.4914_4917delβ(p.Asn1638LysfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,044 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. L1637L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001378454.1 frameshift
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.4914_4917del | p.Asn1638LysfsTer4 | frameshift_variant | 8/23 | ENST00000613296.6 | |
ALMS1 | NM_015120.4 | c.4917_4920del | p.Asn1639LysfsTer4 | frameshift_variant | 8/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALMS1 | ENST00000613296.6 | c.4914_4917del | p.Asn1638LysfsTer4 | frameshift_variant | 8/23 | 1 | NM_001378454.1 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000661 AC: 1AN: 151274Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000201 AC: 5AN: 248262Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 134894
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461770Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727194
GnomAD4 genome ? AF: 0.00000661 AC: 1AN: 151274Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 73852
ClinVar
Submissions by phenotype
Alstrom syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant was found to in trans with other pathogenic variant (3billion dataset). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000550038 / PMID: 25846608). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 22, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | This sequence change creates a premature translational stop signal (p.Asn1639Lysfs*4) 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 (rs779366889, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with Alstrom syndrome and/or cone-rod dystrophy (PMID: 25846608, 26992781). ClinVar contains an entry for this variant (Variation ID: 550038). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at