2-73452863-T-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001378454.1(ALMS1):c.6336T>A(p.Ser2112Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 1,613,406 control chromosomes in the GnomAD database, including 66,846 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 15917 hom., cov: 32)

Exomes 𝑓: 0.24 ( 50929 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0800

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.135518E-7).

BP6

Variant 2-73452863-T-A is Benign according to our data. Variant chr2-73452863-T-A is described in ClinVar as [Benign]. Clinvar id is 383759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.761 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1 link	c.6336T>A	p.Ser2112Arg	missense_variant	Exon 8 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 link	c.6336T>A	p.Ser2112Arg	missense_variant	Exon 8 of 23		NP_055935.4	Q8TCU4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 link	c.6336T>A	p.Ser2112Arg	missense_variant	Exon 8 of 23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.387

AC:

58803

AN:

151986

Hom.:

15854

Cov.:

show subpopulations

Gnomad AFR

AF:

0.768

Gnomad AMI

AF:

0.268

Gnomad AMR

AF:

0.373

Gnomad ASJ

AF:

0.204

Gnomad EAS

AF:

0.00714

Gnomad SAS

AF:

0.150

Gnomad FIN

AF:

0.243

Gnomad MID

AF:

0.212

Gnomad NFE

AF:

0.240

Gnomad OTH

AF:

0.340

GnomAD3 exomes

AF:

0.267

AC:

66163

AN:

248136

Hom.:

12180

AF XY:

0.249

AC XY:

33540

AN XY:

134740

show subpopulations

Gnomad AFR exome

AF:

0.784

Gnomad AMR exome

AF:

0.408

Gnomad ASJ exome

AF:

0.204

Gnomad EAS exome

AF:

0.00608

Gnomad SAS exome

AF:

0.160

Gnomad FIN exome

AF:

0.233

Gnomad NFE exome

AF:

0.237

Gnomad OTH exome

AF:

0.244

GnomAD4 exome

AF:

0.244

AC:

356982

AN:

1461302

Hom.:

50929

Cov.:

AF XY:

0.240

AC XY:

174574

AN XY:

726966

show subpopulations

Gnomad4 AFR exome

AF:

0.781

Gnomad4 AMR exome

AF:

0.409

Gnomad4 ASJ exome

AF:

0.204

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:

0.251

GnomAD4 genome

AF:

0.387

AC:

58929

AN:

152104

Hom.:

15917

Cov.:

AF XY:

0.380

AC XY:

28281

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.768

Gnomad4 AMR

AF:

0.373

Gnomad4 ASJ

AF:

0.204

Gnomad4 EAS

AF:

0.00716

Gnomad4 SAS

AF:

0.151

Gnomad4 FIN

AF:

0.243

Gnomad4 NFE

AF:

0.239

Gnomad4 OTH

AF:

0.336

Alfa

AF:

0.274

Hom.:

2353

Bravo

AF:

0.416

TwinsUK

AF:

0.229

AC:

850

ALSPAC

AF:

0.234

AC:

901

ESP6500AA

AF:

0.740

AC:

2748

ESP6500EA

AF:

0.239

AC:

1956

ExAC

AF:

0.269

AC:

32471

Asia WGS

AF:

0.124

AC:

431

AN:

3478

EpiCase

AF:

0.233

EpiControl

AF:

0.237

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 09, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ser2111Arg in exon 8 of ALMS1: This variant is not expected to have clinical s ignificance because it has been identified in 87.75% (1160/1322) of African chro mosomes by the 1000 Genomes Project (Phase 3; dbSNP rs6724782). -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Alstrom syndrome

Benign:3

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Cardiovascular phenotype

Benign:1

Dec 21, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.12

DANN

Benign

0.66

DEOGEN2

Benign

0.0074

T;.;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0015

LIST_S2

Benign

0.11

T;T;T

MetaRNN

Benign

9.1e-7

T;T;T

MetaSVM

Benign

-0.96

PrimateAI

Benign

0.26

Sift4G

Benign

0.63

T;T;T

Vest4

0.037

ClinPred

0.0043

GERP RS

-5.1

Varity_R

0.026

gMVP

0.019

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