NM_001378454.1:c.6336T>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S2112S) has been classified as Likely 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

Publications

35 publications found

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 Gene-Disease associations (from GenCC):

Alstrom syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Orphanet, Genomics England PanelApp

ALMS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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

GnomAD2 exomes

AF:

0.267

AC:

66163

AN:

248136

AF XY:

0.249

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 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

African (AFR)

AF:

0.781

AC:

26153

AN:

33476

American (AMR)

AF:

0.409

AC:

18247

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.204

AC:

5322

AN:

26128

East Asian (EAS)

AF:

0.0122

AC:

485

AN:

39668

South Asian (SAS)

AF:

0.167

AC:

14429

AN:

86242

European-Finnish (FIN)

AF:

0.232

AC:

12330

AN:

53244

Middle Eastern (MID)

AF:

0.244

AC:

1407

AN:

5768

European-Non Finnish (NFE)

AF:

0.237

AC:

263456

AN:

1111736

Other (OTH)

AF:

0.251

AC:

15153

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

15759

31518

47278

63037

78796

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9050

18100

27150

36200

45250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.387

AC:

58929

AN:

152104

Hom.:

15917

Cov.:

AF XY:

0.380

AC XY:

28281

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.768

AC:

31883

AN:

41506

American (AMR)

AF:

0.373

AC:

5703

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.204

AC:

710

AN:

3472

East Asian (EAS)

AF:

0.00716

AC:

AN:

5170

South Asian (SAS)

AF:

0.151

AC:

728

AN:

4820

European-Finnish (FIN)

AF:

0.243

AC:

2574

AN:

10572

Middle Eastern (MID)

AF:

0.221

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.239

AC:

16276

AN:

67964

Other (OTH)

AF:

0.336

AC:

709

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1432

2863

4295

5726

7158

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

476

952

1428

1904

2380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

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

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. -

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). -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Alstrom syndrome

Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

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

(source)

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

PhyloP100

-0.080

PrimateAI

Benign

0.26

Sift4G

Benign

0.63

T;T;T

Vest4

0.037

ClinPred

0.0043

GERP RS

-5.1

PromoterAI

0.0020

Neutral

(source)

Varity_R

0.026

gMVP

0.019

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over