rs1052161

Positions:

Variant summary

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

The NM_001378454.1(ALMS1):c.12089G>A(p.Arg4030Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.626 in 1,613,740 control chromosomes in the GnomAD database, including 320,677 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar.

Frequency

Genomes: 𝑓 0.56 ( 25093 hom., cov: 32)

Exomes 𝑓: 0.63 ( 295584 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -1.72

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=7.496577E-7).

BP6

Variant 2-73601411-G-A is Benign according to our data. Variant chr2-73601411-G-A is described in ClinVar as [Benign]. Clinvar id is 383764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.726 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1 linkuse as main transcript	c.12089G>A	p.Arg4030Lys	missense_variant	19/23	ENST00000613296.6
ALMS1	NM_015120.4 linkuse as main transcript	c.12092G>A	p.Arg4031Lys	missense_variant	19/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6 linkuse as main transcript	c.12089G>A	p.Arg4030Lys	missense_variant	19/23	1	NM_001378454.1	P3	Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.556

AC:

84422

AN:

151928

Hom.:

25095

Cov.:

show subpopulations

Gnomad AFR

AF:

0.322

Gnomad AMI

AF:

0.678

Gnomad AMR

AF:

0.658

Gnomad ASJ

AF:

0.667

Gnomad EAS

AF:

0.745

Gnomad SAS

AF:

0.673

Gnomad FIN

AF:

0.629

Gnomad MID

AF:

0.675

Gnomad NFE

AF:

0.632

Gnomad OTH

AF:

0.587

GnomAD3 exomes

AF:

0.641

AC:

159886

AN:

249530

Hom.:

52455

AF XY:

0.643

AC XY:

86987

AN XY:

135192

show subpopulations

Gnomad AFR exome

AF:

0.311

Gnomad AMR exome

AF:

0.727

Gnomad ASJ exome

AF:

0.683

Gnomad EAS exome

AF:

0.756

Gnomad SAS exome

AF:

0.670

Gnomad FIN exome

AF:

0.627

Gnomad NFE exome

AF:

0.632

Gnomad OTH exome

AF:

0.652

GnomAD4 exome

AF:

0.633

AC:

924990

AN:

1461694

Hom.:

295584

Cov.:

AF XY:

0.634

AC XY:

460907

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.305

Gnomad4 AMR exome

AF:

0.715

Gnomad4 ASJ exome

AF:

0.683

Gnomad4 EAS exome

AF:

0.734

Gnomad4 SAS exome

AF:

0.664

Gnomad4 FIN exome

AF:

0.632

Gnomad4 NFE exome

AF:

0.632

Gnomad4 OTH exome

AF:

0.638

GnomAD4 genome

AF:

0.555

AC:

84438

AN:

152046

Hom.:

25093

Cov.:

AF XY:

0.562

AC XY:

41740

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.321

Gnomad4 AMR

AF:

0.657

Gnomad4 ASJ

AF:

0.667

Gnomad4 EAS

AF:

0.745

Gnomad4 SAS

AF:

0.672

Gnomad4 FIN

AF:

0.629

Gnomad4 NFE

AF:

0.632

Gnomad4 OTH

AF:

0.586

Alfa

AF:

0.626

Hom.:

78697

Bravo

AF:

0.546

TwinsUK

AF:

0.634

AC:

2350

ALSPAC

AF:

0.634

AC:

2442

ESP6500AA

AF:

0.340

AC:

1498

ESP6500EA

AF:

0.637

AC:

5479

ExAC

AF:

0.631

AC:

76544

Asia WGS

AF:

0.698

AC:

2428

AN:

3478

EpiCase

AF:

0.643

EpiControl

AF:

0.635

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Arg4029Lys in exon 19 of ALMS1: This variant is not expected to have clinical significance because it has been identified in 75.39% (6458/8566) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs1052161). -

Alstrom syndrome

Benign:3

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	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

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

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.010

DANN

Benign

0.28

DEOGEN2

Benign

0.0089

T;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0035

LIST_S2

Benign

0.12

T;T

MetaRNN

Benign

7.5e-7

T;T

MetaSVM

Benign

-0.97

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.37

Sift4G

Benign

0.98

T;T

Vest4

0.0090

ClinPred

0.0051

GERP RS

-6.3

Varity_R

0.032

gMVP

0.077

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