chr2-73489683-G-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.7724G>A(p.Ser2575Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 1,613,854 control chromosomes in the GnomAD database, including 16,134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2575G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.12 ( 1271 hom., cov: 32)

Exomes 𝑓: 0.14 ( 14863 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.36

Publications

34 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=0.0017927587).

BP6

Variant 2-73489683-G-A is Benign according to our data. Variant chr2-73489683-G-A is described in ClinVar as Benign. ClinVar VariationId is 383774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.21 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1 link	c.7724G>A	p.Ser2575Asn	missense_variant	Exon 10 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 link	c.7724G>A	p.Ser2575Asn	missense_variant	Exon 10 of 23		NP_055935.4	Q8TCU4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 link	c.7724G>A	p.Ser2575Asn	missense_variant	Exon 10 of 23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.125

AC:

18957

AN:

151956

Hom.:

1272

Cov.:

show subpopulations

Gnomad AFR

AF:

0.101

Gnomad AMI

AF:

0.0428

Gnomad AMR

AF:

0.0808

Gnomad ASJ

AF:

0.137

Gnomad EAS

AF:

0.221

Gnomad SAS

AF:

0.176

Gnomad FIN

AF:

0.149

Gnomad MID

AF:

0.140

Gnomad NFE

AF:

0.135

Gnomad OTH

AF:

0.117

GnomAD2 exomes

AF:

0.134

AC:

33514

AN:

249504

AF XY:

0.139

show subpopulations

Gnomad AFR exome

AF:

0.101

Gnomad AMR exome

AF:

0.0523

Gnomad ASJ exome

AF:

0.135

Gnomad EAS exome

AF:

0.214

Gnomad FIN exome

AF:

0.158

Gnomad NFE exome

AF:

0.137

Gnomad OTH exome

AF:

0.134

GnomAD4 exome

AF:

0.139

AC:

203585

AN:

1461778

Hom.:

14863

Cov.:

AF XY:

0.141

AC XY:

102416

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.107

AC:

3568

AN:

33480

American (AMR)

AF:

0.0546

AC:

2444

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.133

AC:

3464

AN:

26136

East Asian (EAS)

AF:

0.240

AC:

9541

AN:

39700

South Asian (SAS)

AF:

0.169

AC:

14545

AN:

86258

European-Finnish (FIN)

AF:

0.154

AC:

8241

AN:

53358

Middle Eastern (MID)

AF:

0.146

AC:

842

AN:

5768

European-Non Finnish (NFE)

AF:

0.137

AC:

152890

AN:

1111960

Other (OTH)

AF:

0.133

AC:

8050

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

10828

21656

32483

43311

54139

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5556

11112

16668

22224

27780

<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:

0.125

AC:

18961

AN:

152076

Hom.:

1271

Cov.:

AF XY:

0.125

AC XY:

9296

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.101

AC:

4200

AN:

41494

American (AMR)

AF:

0.0807

AC:

1233

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.137

AC:

475

AN:

3468

East Asian (EAS)

AF:

0.221

AC:

1139

AN:

5162

South Asian (SAS)

AF:

0.175

AC:

842

AN:

4812

European-Finnish (FIN)

AF:

0.149

AC:

1571

AN:

10564

Middle Eastern (MID)

AF:

0.137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.135

AC:

9165

AN:

67976

Other (OTH)

AF:

0.122

AC:

257

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

842

1685

2527

3370

4212

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

234

468

702

936

1170

<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:

0.133

Hom.:

6542

Bravo

AF:

0.118

TwinsUK

AF:

0.144

AC:

535

ALSPAC

AF:

0.141

AC:

542

ESP6500AA

AF:

0.0982

AC:

376

ESP6500EA

AF:

0.130

AC:

1073

ExAC

AF:

0.138

AC:

16617

Asia WGS

AF:

0.182

AC:

631

AN:

3478

EpiCase

AF:

0.133

EpiControl

AF:

0.133

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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 specified

Benign:2

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.Ser2574Asn in exon 10 of ALMS1: This variant is not expected to have clinical significance because it has been identified in 21.64% (1866/8622) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs3820700). -

Sep 23, 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. -

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

0.28

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.033

T;.;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.77

T;T;T

MetaRNN

Benign

0.0018

T;T;T

MetaSVM

Benign

-0.97

PhyloP100

2.4

PrimateAI

Benign

0.45

Sift4G

Uncertain

0.0050

D;D;D

Vest4

0.21

ClinPred

0.013

GERP RS

4.5

Varity_R

0.097

gMVP

0.082

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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