chr2-73450706-A-G

Position:

chr2-73450706-A-G

Variant summary

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

The NM_001378454.1(ALMS1):c.4179A>G(p.Gln1393Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 1,612,754 control chromosomes in the GnomAD database, including 61,871 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 13508 hom., cov: 31)

Exomes 𝑓: 0.24 ( 48363 hom. )

Consequence

ALMS1
NM_001378454.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -2.99

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 2-73450706-A-G is Benign according to our data. Variant chr2-73450706-A-G is described in ClinVar as [Benign]. Clinvar id is 383757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.99 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.691 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.4179A>G	p.Gln1393Gln	synonymous_variant	8/23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 linkuse as main transcript	c.4179A>G	p.Gln1393Gln	synonymous_variant	8/23		NP_055935.4	Q8TCU4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 linkuse as main transcript	c.4179A>G	p.Gln1393Gln	synonymous_variant	8/23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.365

AC:

55126

AN:

150874

Hom.:

13453

Cov.:

show subpopulations

Gnomad AFR

AF:

0.697

Gnomad AMI

AF:

0.268

Gnomad AMR

AF:

0.365

Gnomad ASJ

AF:

0.159

Gnomad EAS

AF:

0.00702

Gnomad SAS

AF:

0.151

Gnomad FIN

AF:

0.246

Gnomad MID

AF:

0.202

Gnomad NFE

AF:

0.239

Gnomad OTH

AF:

0.324

GnomAD3 exomes

AF:

0.259

AC:

64628

AN:

249284

Hom.:

11272

AF XY:

0.243

AC XY:

32840

AN XY:

135230

show subpopulations

Gnomad AFR exome

AF:

0.713

Gnomad AMR exome

AF:

0.403

Gnomad ASJ exome

AF:

0.151

Gnomad EAS exome

AF:

0.00607

Gnomad SAS exome

AF:

0.160

Gnomad FIN exome

AF:

0.233

Gnomad NFE exome

AF:

0.236

Gnomad OTH exome

AF:

0.237

GnomAD4 exome

AF:

0.241

AC:

351815

AN:

1461762

Hom.:

48363

Cov.:

AF XY:

0.237

AC XY:

172163

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.704

Gnomad4 AMR exome

AF:

0.403

Gnomad4 ASJ exome

AF:

0.152

Gnomad4 EAS exome

AF:

0.0122

Gnomad4 SAS exome

AF:

0.167

Gnomad4 FIN exome

AF:

0.232

Gnomad4 NFE exome

AF:

0.237

Gnomad4 OTH exome

AF:

0.242

GnomAD4 genome

AF:

0.366

AC:

55244

AN:

150992

Hom.:

13508

Cov.:

AF XY:

0.361

AC XY:

26602

AN XY:

73740

show subpopulations

Gnomad4 AFR

AF:

0.698

Gnomad4 AMR

AF:

0.366

Gnomad4 ASJ

AF:

0.159

Gnomad4 EAS

AF:

0.00704

Gnomad4 SAS

AF:

0.152

Gnomad4 FIN

AF:

0.246

Gnomad4 NFE

AF:

0.239

Gnomad4 OTH

AF:

0.321

Alfa

AF:

0.272

Hom.:

8611

Bravo

AF:

0.392

Asia WGS

AF:

0.119

AC:

414

AN:

3478

EpiCase

AF:

0.231

EpiControl

AF:

0.236

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Gln1392Gln 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 78.59% (1039/1322) of African chromosomes by the 1000 Genomes Project (Phase 3; dbSNP rs6546836). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 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. -

Alstrom syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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

0.0080

DANN

Benign

0.22

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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