rs112034360

Positions:

chr2-73450421-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000613296.6(ALMS1):c.3894A>G(p.Gln1298=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.053 in 1,612,926 control chromosomes in the GnomAD database, including 2,615 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.058 ( 305 hom., cov: 32)

Exomes 𝑓: 0.052 ( 2310 hom. )

Consequence

ALMS1
ENST00000613296.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -3.36

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 2-73450421-A-G is Benign according to our data. Variant chr2-73450421-A-G is described in ClinVar as [Benign]. Clinvar id is 383756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.36 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALMS1	NM_001378454.1 linkuse as main transcript	c.3894A>G	p.Gln1298=	synonymous_variant	8/23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 linkuse as main transcript	c.3897A>G	p.Gln1299=	synonymous_variant	8/23		NP_055935.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 linkuse as main transcript	c.3894A>G	p.Gln1298=	synonymous_variant	8/23	1	NM_001378454.1	ENSP00000482968	P3	Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.0582

AC:

8796

AN:

151030

Hom.:

305

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0751

Gnomad AMI

AF:

0.00881

Gnomad AMR

AF:

0.0310

Gnomad ASJ

AF:

0.0292

Gnomad EAS

AF:

0.000581

Gnomad SAS

AF:

0.0132

Gnomad FIN

AF:

0.0906

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.0593

Gnomad OTH

AF:

0.0513

GnomAD3 exomes

AF:

0.0453

AC:

11284

AN:

249262

Hom.:

374

AF XY:

0.0436

AC XY:

5901

AN XY:

135216

show subpopulations

Gnomad AFR exome

AF:

0.0707

Gnomad AMR exome

AF:

0.0222

Gnomad ASJ exome

AF:

0.0322

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.0123

Gnomad FIN exome

AF:

0.0833

Gnomad NFE exome

AF:

0.0586

Gnomad OTH exome

AF:

0.0500

GnomAD4 exome

AF:

0.0525

AC:

76674

AN:

1461780

Hom.:

2310

Cov.:

AF XY:

0.0512

AC XY:

37217

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.0702

Gnomad4 AMR exome

AF:

0.0247

Gnomad4 ASJ exome

AF:

0.0325

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0116

Gnomad4 FIN exome

AF:

0.0820

Gnomad4 NFE exome

AF:

0.0576

Gnomad4 OTH exome

AF:

0.0473

GnomAD4 genome

AF:

0.0582

AC:

8796

AN:

151146

Hom.:

305

Cov.:

AF XY:

0.0579

AC XY:

4277

AN XY:

73844

show subpopulations

Gnomad4 AFR

AF:

0.0749

Gnomad4 AMR

AF:

0.0309

Gnomad4 ASJ

AF:

0.0292

Gnomad4 EAS

AF:

0.000583

Gnomad4 SAS

AF:

0.0128

Gnomad4 FIN

AF:

0.0906

Gnomad4 NFE

AF:

0.0593

Gnomad4 OTH

AF:

0.0508

Alfa

AF:

0.0596

Hom.:

147

Bravo

AF:

0.0533

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.0493

EpiControl

AF:

0.0504

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 21, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Gln1297Gln in exon 8 of ALMS1: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 7.82% (517/6614) of Finnish chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs112034360). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Alstrom syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.0040

DANN

Benign

0.15

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over