2-73453381-G-C

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.6854G>C(p.Arg2285Pro) 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 1,613,278 control chromosomes in the GnomAD database, including 66,720 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R2285H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.39 ( 15845 hom., cov: 31)

Exomes 𝑓: 0.24 ( 50875 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.13

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=1.2201531E-6).

BP6

Variant 2-73453381-G-C is Benign according to our data. Variant chr2-73453381-G-C is described in ClinVar as Benign. ClinVar VariationId is 383760.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.6854G>C	p.Arg2285Pro	missense_variant	Exon 8 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 link	c.6854G>C	p.Arg2285Pro	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.6854G>C	p.Arg2285Pro	missense_variant	Exon 8 of 23	1	NM_001378454.1	ENSP00000482968.1

Frequencies

GnomAD3 genomes

AF:

0.387

AC:

58584

AN:

151550

Hom.:

15782

Cov.:

show subpopulations

Gnomad AFR

AF:

0.768

Gnomad AMI

AF:

0.269

Gnomad AMR

AF:

0.372

Gnomad ASJ

AF:

0.205

Gnomad EAS

AF:

0.00713

Gnomad SAS

AF:

0.150

Gnomad FIN

AF:

0.242

Gnomad MID

AF:

0.210

Gnomad NFE

AF:

0.239

Gnomad OTH

AF:

0.341

GnomAD2 exomes

AF:

0.267

AC:

66335

AN:

248434

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:

0.00607

Gnomad FIN exome

AF:

0.233

Gnomad NFE exome

AF:

0.237

Gnomad OTH exome

AF:

0.244

GnomAD4 exome

AF:

0.244

AC:

356869

AN:

1461610

Hom.:

50875

Cov.:

AF XY:

0.240

AC XY:

174511

AN XY:

727100

show subpopulations

African (AFR)

AF:

0.781

AC:

26148

AN:

33478

American (AMR)

AF:

0.408

AC:

18252

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.204

AC:

5321

AN:

26130

East Asian (EAS)

AF:

0.0122

AC:

485

AN:

39690

South Asian (SAS)

AF:

0.167

AC:

14429

AN:

86252

European-Finnish (FIN)

AF:

0.232

AC:

12356

AN:

53346

Middle Eastern (MID)

AF:

0.244

AC:

1406

AN:

5768

European-Non Finnish (NFE)

AF:

0.237

AC:

263324

AN:

1111874

Other (OTH)

AF:

0.251

AC:

15148

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

15762

31523

47285

63046

78808

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9048

18096

27144

36192

45240

<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:

58711

AN:

151668

Hom.:

15845

Cov.:

AF XY:

0.380

AC XY:

28163

AN XY:

74074

show subpopulations

African (AFR)

AF:

0.768

AC:

31769

AN:

41348

American (AMR)

AF:

0.373

AC:

5671

AN:

15204

Ashkenazi Jewish (ASJ)

AF:

0.205

AC:

710

AN:

3468

East Asian (EAS)

AF:

0.00715

AC:

AN:

5176

South Asian (SAS)

AF:

0.151

AC:

724

AN:

4804

European-Finnish (FIN)

AF:

0.242

AC:

2536

AN:

10460

Middle Eastern (MID)

AF:

0.219

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.239

AC:

16244

AN:

67896

Other (OTH)

AF:

0.337

AC:

711

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1391

2782

4174

5565

6956

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:

0.222

Hom.:

3112

Bravo

AF:

0.416

TwinsUK

AF:

0.230

AC:

851

ALSPAC

AF:

0.234

AC:

901

ESP6500AA

AF:

0.742

AC:

2723

ESP6500EA

AF:

0.239

AC:

1952

ExAC

AF:

0.269

AC:

32512

Asia WGS

AF:

0.124

AC:

432

AN:

3476

EpiCase

AF:

0.232

EpiControl

AF:

0.237

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alstrom syndrome

Benign:5

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

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:4

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. -

Clinical Genetics, Academic Medical Center

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

- -

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.Arg2284Pro in exon 8 of ALMS1: This variant is not expected to have clinical s ignificance because it has been identified in 87.82% (1161/1322) of African chro mosomes by the 1000 Genomes Project (Phase 3; dbSNP rs6546839). -

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

0.053

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.0072

T;.;.

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.40

T;T;T

MetaRNN

Benign

0.0000012

T;T;T

MetaSVM

Benign

-0.99

PhyloP100

3.1

PrimateAI

Benign

0.36

Sift4G

Benign

1.0

T;T;T

Vest4

0.064

ClinPred

0.013

GERP RS

5.5

Varity_R

0.19

gMVP

0.22

Mutation Taster

=97/3

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