chr2-73448398-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001378454.1(ALMS1):c.1871A>G(p.His624Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0206 in 1,614,026 control chromosomes in the GnomAD database, including 423 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. H624H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.016 ( 24 hom., cov: 32)

Exomes 𝑓: 0.021 ( 399 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.281

Publications

12 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=0.00374794).

BP6

Variant 2-73448398-A-G is Benign according to our data. Variant chr2-73448398-A-G is described in ClinVar as Benign. ClinVar VariationId is 240984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0158 (2412/152256) while in subpopulation NFE AF = 0.0261 (1774/67984). AF 95% confidence interval is 0.0251. There are 24 homozygotes in GnomAd4. There are 1163 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1 link	c.1871A>G	p.His624Arg	missense_variant	Exon 8 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 link	c.1871A>G	p.His624Arg	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.1871A>G	p.His624Arg	missense_variant	Exon 8 of 23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.0159

AC:

2413

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00420

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0106

Gnomad ASJ

AF:

0.0110

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.0200

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0261

Gnomad OTH

AF:

0.0153

GnomAD2 exomes

AF:

0.0169

AC:

4208

AN:

249146

AF XY:

0.0164

show subpopulations

Gnomad AFR exome

AF:

0.00484

Gnomad AMR exome

AF:

0.00898

Gnomad ASJ exome

AF:

0.00656

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.0178

Gnomad NFE exome

AF:

0.0279

Gnomad OTH exome

AF:

0.0175

GnomAD4 exome

AF:

0.0211

AC:

30821

AN:

1461770

Hom.:

399

Cov.:

AF XY:

0.0204

AC XY:

14849

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.00305

AC:

102

AN:

33470

American (AMR)

AF:

0.00997

AC:

446

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00758

AC:

198

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00328

AC:

283

AN:

86258

European-Finnish (FIN)

AF:

0.0188

AC:

1006

AN:

53408

Middle Eastern (MID)

AF:

0.0133

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0248

AC:

27554

AN:

1111926

Other (OTH)

AF:

0.0191

AC:

1154

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

1973

3946

5918

7891

9864

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

948

1896

2844

3792

4740

<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:

0.0158

AC:

2412

AN:

152256

Hom.:

Cov.:

AF XY:

0.0156

AC XY:

1163

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00419

AC:

174

AN:

41570

American (AMR)

AF:

0.0106

AC:

162

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0110

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.00290

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0200

AC:

212

AN:

10616

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0261

AC:

1774

AN:

67984

Other (OTH)

AF:

0.0147

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

120

240

359

479

599

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0220

Hom.:

Bravo

AF:

0.0145

TwinsUK

AF:

0.0205

AC:

ALSPAC

AF:

0.0218

AC:

ESP6500AA

AF:

0.00402

AC:

ESP6500EA

AF:

0.0255

AC:

209

ExAC

AF:

0.0190

AC:

2291

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

May 18, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26104972) -

Dec 29, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 10, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The ALMS1 c.1868A>G (p.His623Arg, alternative name c.1874A>G) variant involves the alteration of a non-conserved nucleotide and 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome for this variant. This variant was found in 2291/120716 control chromosomes (31 homozygotes) at a frequency of 0.0189784, which is approximately 8 times the estimated maximal expected allele frequency of a pathogenic ALMS1 variant (0.0022361), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories classified this variant as "likely benign/benign." Therefore, the variant of interest has been classified as "benign." -

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.His623Arg in exon 8 of ALMS1: This variant is not expected to have clinical si gnificance because it has been identified in 2.88% (1921/66716) of European chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs41291187). -

Alstrom syndrome

Benign:3

Dec 02, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Monogenic diabetes

Benign:1

Jan 25, 2019

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

ACMG criteria: BP4 (9 predictors, REVEL=0.012), BA1 (2.8% in EurNF in gnomAD), BS2 (31 homozygotes in ExAC, 54 homozygotes in gnomAD), BP1 (known variants are truncating)=benign -

Cardiovascular phenotype

Benign:1

Dec 24, 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

0.083

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.54

CADD

Benign

0.94

(source)

DANN

Benign

0.31

DEOGEN2

Benign

0.014

T;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.055

LIST_S2

Benign

0.33

T;T;T

MetaRNN

Benign

0.0037

T;T;T

MetaSVM

Benign

-1.0

PhyloP100

-0.28

PrimateAI

Benign

0.26

Sift4G

Benign

0.34

T;T;T

Vest4

0.029

ClinPred

0.00091

GERP RS

-2.5

Varity_R

0.029

gMVP

0.055

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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