rs771459937

Positions:

• chr2-73448697-AT-A
• chr2-73448697-AT-ATT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001378454.1(ALMS1):​c.2176del​(p.Tyr726ThrfsTer53) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,616 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ALMS1 NM_001378454.1 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.0420

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]

ACMG classification

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 2-73448697-AT-A is Pathogenic according to our data. Variant chr2-73448697-AT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1982236.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
ALMS1	NM_001378454.1	c.2176del	p.Tyr726ThrfsTer53	frameshift_variant	8/23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4	c.2179del	p.Tyr727ThrfsTer53	frameshift_variant	8/23		NP_055935.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6	c.2176del	p.Tyr726ThrfsTer53	frameshift_variant	8/23	1	NM_001378454.1	ENSP00000482968	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000804 AC: 2 AN: 248784 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134956

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452616 Hom.: 0 Cov.: 82 AF XY: 0.00 AC XY: 0 AN XY: 722292

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000456

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alstrom syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 09, 2020	The c.2179delT, p.Tyr727ThrfsX53 variant in ALMS1 has not been previously reported in individuals with Alstrom syndrome but has been identified in 0.006% (2/34512) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Please note that due to a discrepancy between the NM_015120.4 transcript and the GRCh37/hg19 genomic sequence in which NM_015120.4 transcript has 2 extra codons and 6 extra nucleotides. Therefore, this variant may also be referred to as c.2173delT, p.Tyr725thrfsX53. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 727 and leads to a premature termination codon 53 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the ALMS1 gene is an established disease mechanism in autosomal recessive Alstrom syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Alstrom syndrome. ACMG/AMP Criteria applied: PVS1, PM2. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 04, 2022	This sequence change creates a premature translational stop signal (p.Tyr727Thrfs*53) 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). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with ALMS1-related conditions. This variant is present in population databases (rs771459937, gnomAD 0.006%). -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs771459937; hg19: chr2-73675824;