rs760264695

Variant names:

• chr2-73599501-T-TGTTA
• rs760264695
• NM_001378454.1:c.11648_11649insGTTA

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.11648_11649insGTTA​(p.Asn3884LeufsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,461,328 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: ALMS1 NM_001378454.1 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.903

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 2-73599501-T-TGTTA is Pathogenic according to our data. Variant chr2-73599501-T-TGTTA is described in ClinVar as [Pathogenic]. Clinvar id is 550627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1	c.11648_11649insGTTA	p.Asn3884LeufsTer9	frameshift_variant	Exon 17 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4	c.11648_11649insGTTA	p.Asn3884LeufsTer9	frameshift_variant	Exon 17 of 23		NP_055935.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6	c.11648_11649insGTTA	p.Asn3884LeufsTer9	frameshift_variant	Exon 17 of 23	1	NM_001378454.1	ENSP00000482968.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 248960 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135070

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1461328 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 726976

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alstrom syndrome Pathogenic:4

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Asn3885Leufs*9) 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 (rs760264695, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with Alstrom syndrome (PMID: 25846608, 26111748, 30064963). ClinVar contains an entry for this variant (Variation ID: 550627). For these reasons, this variant has been classified as Pathogenic. -

Feb 17, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 08, 2017

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2022

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The heterozygous p.Asn3883LeufsTer9 variant in ALMS1 was identified by our study in the compound heterozygous state, along with another pathogenic variant, in 1 individual with Alstrom syndrome. The variant has been reported in 6 individuals of unknown ethnicity with Alstrom syndrome (PMID: 26704672, 28610912, 26111748), and has been identified in 0.003% (3/112826) of European non-Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs760264695). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 3883 and leads to a premature termination codon 9 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. The presence of this variant in combination with reported likely pathogenic variants and in 6 individuals with Alstrom syndrome increases the likelihood that the p.Asn3883LeufsTer9 variant is pathogenic (VariationID: 556350, 553694; PMID: 26704672, 28610912, 26111748). In summary, this variant meets criteria to be classified as pathogenic for Alstrom syndrome in an autosomal recessive manner based on the predicted impact of the variant and its occurrence in trans with other likely pathogenic variants. ACMG/AMP Criteria applied: PVS1, PM2, PM3 (Richards 2015). -

Cardiovascular phenotype Pathogenic:1

Aug 27, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.11651_11652insGTTA pathogenic mutation, located in coding exon 17 of the ALMS1 gene, results from an insertion of 4 nucleotides at position 11651, causing a translational frameshift with a predicted alternate stop codon (p.N3885Lfs*9). This variant has been reported in an Alstrom syndrome cohort with limited clinical details provided (Marshall JD et al. Hum. Mutat., 2015 Jul;36:660-8). 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: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs760264695; hg19: chr2-73826628;