2-73490440-G-T

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.8481G>T(p.Arg2827Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 1,613,828 control chromosomes in the GnomAD database, including 65,462 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. R2827R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.38 ( 15450 hom., cov: 32)

Exomes 𝑓: 0.24 ( 50012 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0230

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:

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=9.597444E-7).

BP6

Variant 2-73490440-G-T is Benign according to our data. Variant chr2-73490440-G-T is described in ClinVar as Benign. ClinVar VariationId is 383761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.748 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1 link	c.8481G>T	p.Arg2827Ser	missense_variant	Exon 10 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 link	c.8481G>T	p.Arg2827Ser	missense_variant	Exon 10 of 23		NP_055935.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 link	c.8481G>T	p.Arg2827Ser	missense_variant	Exon 10 of 23	1	NM_001378454.1	ENSP00000482968.1

Frequencies

GnomAD3 genomes

AF:

0.382

AC:

57998

AN:

151928

Hom.:

15391

Cov.:

show subpopulations

Gnomad AFR

AF:

0.755

Gnomad AMI

AF:

0.268

Gnomad AMR

AF:

0.371

Gnomad ASJ

AF:

0.159

Gnomad EAS

AF:

0.00713

Gnomad SAS

AF:

0.150

Gnomad FIN

AF:

0.243

Gnomad MID

AF:

0.210

Gnomad NFE

AF:

0.239

Gnomad OTH

AF:

0.334

GnomAD2 exomes

AF:

0.263

AC:

65530

AN:

249074

AF XY:

0.246

show subpopulations

Gnomad AFR exome

AF:

0.770

Gnomad AMR exome

AF:

0.407

Gnomad ASJ exome

AF:

0.151

Gnomad EAS exome

AF:

0.00607

Gnomad FIN exome

AF:

0.232

Gnomad NFE exome

AF:

0.236

Gnomad OTH exome

AF:

0.238

GnomAD4 exome

AF:

0.242

AC:

354192

AN:

1461778

Hom.:

50012

Cov.:

AF XY:

0.238

AC XY:

173196

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.766

AC:

25657

AN:

33480

American (AMR)

AF:

0.407

AC:

18182

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.151

AC:

3959

AN:

26134

East Asian (EAS)

AF:

0.0122

AC:

485

AN:

39698

South Asian (SAS)

AF:

0.167

AC:

14419

AN:

86256

European-Finnish (FIN)

AF:

0.231

AC:

12343

AN:

53364

Middle Eastern (MID)

AF:

0.244

AC:

1406

AN:

5768

European-Non Finnish (NFE)

AF:

0.236

AC:

262879

AN:

1111970

Other (OTH)

AF:

0.246

AC:

14862

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

16543

33087

49630

66174

82717

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9016

18032

27048

36064

45080

<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:

0.382

AC:

58120

AN:

152050

Hom.:

15450

Cov.:

AF XY:

0.375

AC XY:

27906

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.755

AC:

31336

AN:

41482

American (AMR)

AF:

0.372

AC:

5676

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.159

AC:

550

AN:

3468

East Asian (EAS)

AF:

0.00715

AC:

AN:

5174

South Asian (SAS)

AF:

0.151

AC:

725

AN:

4806

European-Finnish (FIN)

AF:

0.243

AC:

2569

AN:

10576

Middle Eastern (MID)

AF:

0.218

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.239

AC:

16224

AN:

67968

Other (OTH)

AF:

0.330

AC:

695

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1392

2784

4175

5567

6959

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

474

948

1422

1896

2370

<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:

0.267

Hom.:

29260

Bravo

AF:

0.410

TwinsUK

AF:

0.229

AC:

849

ALSPAC

AF:

0.232

AC:

896

ESP6500AA

AF:

0.727

AC:

2699

ESP6500EA

AF:

0.237

AC:

1935

ExAC

AF:

0.266

AC:

32091

Asia WGS

AF:

0.124

AC:

430

AN:

3478

EpiCase

AF:

0.231

EpiControl

AF:

0.236

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

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

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.Arg2826Ser in exon 10 of ALMS1: This variant is not expected to have clinical significance because it has been identified in 85.78% (1134/1322) of African chr omosomes by the 1000 Genomes Project (Phase 3; dbSNP rs2056486).

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.

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

0.080

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.64

CADD

Benign

1.0

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.0063

T;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0016

LIST_S2

Benign

0.17

T;T;T

MetaRNN

Benign

9.6e-7

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;.;.

PhyloP100

0.023

PrimateAI

Benign

0.27

PROVEAN

Benign

0.0

.;.;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.;.

Sift4G

Benign

1.0

T;T;T

Vest4

0.018

ClinPred

0.00046

GERP RS

0.26

Varity_R

0.081

gMVP

0.017

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