rs755616266

Variant names:

• chr2-73572702-CAG-C
• rs755616266
• NM_001378454.1:c.10828_10829delAG

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.10828_10829delAG​(p.Arg3610AlafsTer6) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000062 in 1,613,948 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: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ALMS1 NM_001378454.1 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.87

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 2-73572702-CAG-C is Pathogenic according to our data. Variant chr2-73572702-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 552413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-73572702-CAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1	c.10828_10829delAG	p.Arg3610AlafsTer6	frameshift_variant	Exon 16 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4	c.10828_10829delAG	p.Arg3610AlafsTer6	frameshift_variant	Exon 16 of 23		NP_055935.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6	c.10828_10829delAG	p.Arg3610AlafsTer6	frameshift_variant	Exon 16 of 23	1	NM_001378454.1	ENSP00000482968.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000201 AC: 5 AN: 248652 Hom.: 0 AF XY: 0.0000297 AC XY: 4 AN XY: 134858

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000279

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: 0.00000547 AC: 8 AN: 1461754 Hom.: 0 AF XY: 0.00000413 AC XY: 3 AN XY: 727168

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74336

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alstrom syndrome Pathogenic:6

-

Department of Pediatrics, National Cheng-Kung University Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 23, 2024

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.Arg3611Alafs*6) 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 (rs755616266, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with clinical features of Alström syndrome (PMID: 17594715, 26010121, 29720996). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 552413). For these reasons, this variant has been classified as Pathogenic. -

Dec 14, 2024

Department of Endocrinology and Genetics, Fuzhou Children’s Hospital of Fujian Medical University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 09, 2017

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2025

SingHealth Duke-NUS Institute of Precision Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant is predicted to cause nonsense-mediated decay in a gene where LOF is a known cause of pathogenicity (PVS1). Homozygous allele count in gnomAD exomes and genomes are less than 0 (PM2). Variant is found in trans with another pathogenic variant (PM3) -

Nov 10, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs755616266; hg19: chr2-73799829;