rs1085307054

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001378454.1(ALMS1):​c.3781G>T​(p.Glu1261*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Consequence

ALMS1
NM_001378454.1 stop_gained

Scores

2
1
4

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: -0.904
Variant links:
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 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-73450308-G-T is Pathogenic according to our data. Variant chr2-73450308-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ALMS1NM_001378454.1 linkuse as main transcriptc.3781G>T p.Glu1261* stop_gained 8/23 ENST00000613296.6 NP_001365383.1
ALMS1NM_015120.4 linkuse as main transcriptc.3781G>T p.Glu1261* stop_gained 8/23 NP_055935.4 Q8TCU4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ALMS1ENST00000613296.6 linkuse as main transcriptc.3781G>T p.Glu1261* stop_gained 8/231 NM_001378454.1 ENSP00000482968.1 Q8TCU4-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
40
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Alstrom syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitterreference populationSoonchunhyang University Bucheon Hospital, Soonchunhyang University Medical CenterMar 18, 2016- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 06, 2023This sequence change creates a premature translational stop signal (p.Glu1262*) 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ALMS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 225295). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.25
CADD
Uncertain
25
DANN
Uncertain
0.99
Eigen
Benign
-0.13
Eigen_PC
Benign
-0.53
FATHMM_MKL
Benign
0.098
N
MutationTaster
Benign
1.0
A;A;A
Vest4
0.70
GERP RS
-0.70

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1085307054; hg19: chr2-73677435; API