rs1553403917

Variant names:

• chr2-73451171-C-CA
• rs1553403917
• NM_001378454.1:c.4645dupA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001378454.1(ALMS1):​c.4645dupA​(p.Arg1549LysfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. R1549R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALMS1 NM_001378454.1 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.0600
• Publications: 0 publications found

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]

ALMS1 Gene-Disease associations (from GenCC):

• Alstrom syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 11 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 2-73451171-C-CA is Pathogenic according to our data. Variant chr2-73451171-C-CA is described in ClinVar as Pathogenic. ClinVar VariationId is 437922.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1	c.4645dupA	p.Arg1549LysfsTer10	frameshift_variant	Exon 8 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4	c.4645dupA	p.Arg1549LysfsTer10	frameshift_variant	Exon 8 of 23		NP_055935.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6	c.4645dupA	p.Arg1549LysfsTer10	frameshift_variant	Exon 8 of 23	1	NM_001378454.1	ENSP00000482968.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Alstrom syndrome Pathogenic:1

Sep 06, 2017

MAGI'S LAB - Medical Genetics Laboratory, MAGI GROUP

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This homozygous frameshift variation NM_015120.1:c.4648dup;p.(Arg1550Lysfs*10), identified in a patient with Alstrom Syndrome (OMIM# 203800), lies in exon 8 of the ALMS1 gene. A vast majority of reported ALMS1 mutations associated to the syndrome are localized in exon 8 (the largest among the 23 exons of the gene) and are almost all stop codon or frameshift variations resulting in the early termination of the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.060
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1553403917; hg19: chr2-73678298;