rs112034360

chr2-73450421-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001378454.1(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 NM_001378454.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.36

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 -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	UniProt
ALMS1	NM_001378454.1	c.3894A>G	p.Gln1298=	synonymous_variant	8/23	ENST00000613296.6
ALMS1	NM_015120.4	c.3897A>G	p.Gln1299=	synonymous_variant	8/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6	c.3894A>G	p.Gln1298=	synonymous_variant	8/23	1	NM_001378454.1	P3

Frequencies

GnomAD3 genomes AF: 0.0582 AC: 8796 AN: 151030 Hom.: 305 Cov.: 32

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

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.: 40 AF XY: 0.0512 AC XY: 37217 AN XY: 727192

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.: 32 AF XY: 0.0579 AC XY: 4277 AN XY: 73844

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: 35 AN: 3478

EpiCase AF: 0.0493

EpiControl AF: 0.0504

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 21, 2013	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Alstrom syndrome Benign:2

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

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

Other links and lift over

dbSNP: rs112034360; hg19: chr2-73677548; COSMIC: COSV52502774; COSMIC: COSV52502774;