2-73448097-TCTC-TCTCCTC

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PM4_Supporting BP6_Very_Strong BS2

The NM_001378454.1(ALMS1):c.1574_1576dup(p.Pro525dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: ALMS1 NM_001378454.1 inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0440

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 Benign. Variant got -11 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001378454.1. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 2-73448097-T-TCTC is Benign according to our data. Variant chr2-73448097-T-TCTC is described in ClinVar as [Benign]. Clinvar id is 221186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 52960 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1	c.1574_1576dup	p.Pro525dup	inframe_insertion	8/23	ENST00000613296.6
ALMS1	NM_015120.4	c.1577_1579dup	p.Pro526dup	inframe_insertion	8/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6	c.1574_1576dup	p.Pro525dup	inframe_insertion	8/23	1	NM_001378454.1	P3

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.645 AC: 160831 AN: 249214 Hom.: 52960 AF XY: 0.647 AC XY: 87523 AN XY: 135202

Gnomad AFR exome AF: 0.350

Gnomad AMR exome AF: 0.730

Gnomad ASJ exome AF: 0.630

Gnomad EAS exome AF: 0.779

Gnomad SAS exome AF: 0.671

Gnomad FIN exome AF: 0.627

Gnomad NFE exome AF: 0.636

Gnomad OTH exome AF: 0.653

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Asia WGS AF: 0.711 AC: 2472 AN: 3478

EpiCase AF: 0.646

EpiControl AF: 0.639

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 25, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Ser524_Leu525insPro in exon 8 of ALMS1: This variant is not expected to have c linical significance because it has been identified in 77.61% (6676/8602) of Eas t Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broad institute.org; dbSNP rs587621330). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2018

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Alstrom syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 12, 2015

- -

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: rs34628045; hg19: chr2-73675227;