rs34465329

chr2-73601301-G-GT

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001378454.1(ALMS1):c.11979_11980insT(p.Thr3994TyrfsTer54) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALMS1 NM_001378454.1 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.38

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 10 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1	c.11979_11980insT	p.Thr3994TyrfsTer54	frameshift_variant	19/23	ENST00000613296.6
ALMS1	NM_015120.4	c.11982_11983insT	p.Thr3995TyrfsTer54	frameshift_variant	19/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6	c.11979_11980insT	p.Thr3994TyrfsTer54	frameshift_variant	19/23	1	NM_001378454.1	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 74

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34465329; hg19: chr2-73828428;