2-73448542-T-G

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.2015T>G(p.Val672Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.863 in 1,613,818 control chromosomes in the GnomAD database, including 601,917 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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.88 ( 58400 hom., cov: 30)

Exomes 𝑓: 0.86 ( 543517 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.272

Publications

38 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:

ENSG00000295621 (HGNC:):

ENSG00000295621 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=1.2640652E-6).

BP6

Variant 2-73448542-T-G is Benign according to our data. Variant chr2-73448542-T-G is described in ClinVar as Benign. ClinVar VariationId is 504918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.908 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1 link	c.2015T>G	p.Val672Gly	missense_variant	Exon 8 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 link	c.2015T>G	p.Val672Gly	missense_variant	Exon 8 of 23		NP_055935.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 link	c.2015T>G	p.Val672Gly	missense_variant	Exon 8 of 23	1	NM_001378454.1	ENSP00000482968.1

Frequencies

GnomAD3 genomes

AF:

0.876

AC:

133048

AN:

151960

Hom.:

58344

Cov.:

show subpopulations

Gnomad AFR

AF:

0.899

Gnomad AMI

AF:

0.958

Gnomad AMR

AF:

0.921

Gnomad ASJ

AF:

0.817

Gnomad EAS

AF:

0.774

Gnomad SAS

AF:

0.822

Gnomad FIN

AF:

0.852

Gnomad MID

AF:

0.854

Gnomad NFE

AF:

0.868

Gnomad OTH

AF:

0.880

GnomAD2 exomes

AF:

0.865

AC:

215237

AN:

248768

AF XY:

0.860

show subpopulations

Gnomad AFR exome

AF:

0.900

Gnomad AMR exome

AF:

0.949

Gnomad ASJ exome

AF:

0.825

Gnomad EAS exome

AF:

0.783

Gnomad FIN exome

AF:

0.843

Gnomad NFE exome

AF:

0.866

Gnomad OTH exome

AF:

0.866

GnomAD4 exome

AF:

0.862

AC:

1259705

AN:

1461740

Hom.:

543517

Cov.:

AF XY:

0.860

AC XY:

625394

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.894

AC:

29933

AN:

33472

American (AMR)

AF:

0.947

AC:

42321

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.825

AC:

21559

AN:

26130

East Asian (EAS)

AF:

0.760

AC:

30176

AN:

39696

South Asian (SAS)

AF:

0.829

AC:

71496

AN:

86254

European-Finnish (FIN)

AF:

0.847

AC:

45217

AN:

53412

Middle Eastern (MID)

AF:

0.853

AC:

4917

AN:

5766

European-Non Finnish (NFE)

AF:

0.865

AC:

961772

AN:

1111924

Other (OTH)

AF:

0.866

AC:

52314

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

11690

23380

35069

46759

58449

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21260

42520

63780

85040

106300

<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:

0.876

AC:

133166

AN:

152078

Hom.:

58400

Cov.:

AF XY:

0.875

AC XY:

65035

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.899

AC:

37324

AN:

41498

American (AMR)

AF:

0.921

AC:

14065

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.817

AC:

2835

AN:

3470

East Asian (EAS)

AF:

0.774

AC:

3980

AN:

5140

South Asian (SAS)

AF:

0.823

AC:

3960

AN:

4814

European-Finnish (FIN)

AF:

0.852

AC:

9017

AN:

10586

Middle Eastern (MID)

AF:

0.857

AC:

252

AN:

294

European-Non Finnish (NFE)

AF:

0.868

AC:

59006

AN:

67980

Other (OTH)

AF:

0.877

AC:

1853

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

837

1673

2510

3346

4183

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

896

1792

2688

3584

4480

<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:

0.867

Hom.:

186137

Bravo

AF:

0.882

TwinsUK

AF:

0.858

AC:

3180

ALSPAC

AF:

0.862

AC:

3323

ESP6500AA

AF:

0.902

AC:

3459

ESP6500EA

AF:

0.871

AC:

7180

ExAC

AF:

0.863

AC:

104212

Asia WGS

AF:

0.816

AC:

2839

AN:

3478

EpiCase

AF:

0.870

EpiControl

AF:

0.869

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 03, 2017

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. -

Clinical Genetics, Academic Medical Center

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.Val671Gly in exon 8 of ALMS1: This variant is not expected to have clinical si gnificance because it has been identified in 94.88% (10945/11536) of Latino chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs2037814). -

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

0.031

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.22

(source)

DANN

Benign

0.38

DEOGEN2

Benign

0.0061

T;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.00022

LIST_S2

Benign

0.098

T;T;T

MetaRNN

Benign

0.0000013

T;T;T

MetaSVM

Benign

-1.1

PhyloP100

-0.27

PrimateAI

Benign

0.24

Sift4G

Benign

0.63

T;T;T

Vest4

0.062

ClinPred

0.0014

GERP RS

0.15

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.032

gMVP

0.056

Mutation Taster

=99/1

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