rs62151609

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001378454.1(ALMS1):c.5463G>A(p.Pro1821Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00792 in 1,612,522 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0088 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0078 ( 71 hom. )

Consequence

ALMS1
NM_001378454.1 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.873

Publications

2 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 2-73451990-G-A is Benign according to our data. Variant chr2-73451990-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.873 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00877 (1322/150752) while in subpopulation NFE AF = 0.00966 (653/67630). AF 95% confidence interval is 0.00904. There are 8 homozygotes in GnomAd4. There are 720 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1 link	c.5463G>A	p.Pro1821Pro	synonymous_variant	Exon 8 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 link	c.5463G>A	p.Pro1821Pro	synonymous_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.5463G>A	p.Pro1821Pro	synonymous_variant	Exon 8 of 23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.00877

AC:

1321

AN:

150630

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00638

Gnomad AMI

AF:

0.0188

Gnomad AMR

AF:

0.00310

Gnomad ASJ

AF:

0.00145

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00126

Gnomad FIN

AF:

0.0308

Gnomad MID

AF:

0.00340

Gnomad NFE

AF:

0.00964

Gnomad OTH

AF:

0.00435

GnomAD2 exomes

AF:

0.00725

AC:

1804

AN:

248922

AF XY:

0.00708

show subpopulations

Gnomad AFR exome

AF:

0.00531

Gnomad AMR exome

AF:

0.00217

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0276

Gnomad NFE exome

AF:

0.00844

Gnomad OTH exome

AF:

0.00661

GnomAD4 exome

AF:

0.00783

AC:

11452

AN:

1461770

Hom.:

Cov.:

AF XY:

0.00775

AC XY:

5634

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.00702

AC:

235

AN:

33456

American (AMR)

AF:

0.00248

AC:

111

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00142

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00175

AC:

151

AN:

86250

European-Finnish (FIN)

AF:

0.0274

AC:

1463

AN:

53414

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00812

AC:

9033

AN:

1111944

Other (OTH)

AF:

0.00689

AC:

416

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

800

1599

2399

3198

3998

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

316

632

948

1264

1580

<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:

0.00877

AC:

1322

AN:

150752

Hom.:

Cov.:

AF XY:

0.00977

AC XY:

720

AN XY:

73664

show subpopulations

African (AFR)

AF:

0.00639

AC:

262

AN:

41000

American (AMR)

AF:

0.00310

AC:

AN:

15180

Ashkenazi Jewish (ASJ)

AF:

0.00145

AC:

AN:

3440

East Asian (EAS)

AF:

0.00

AC:

AN:

5010

South Asian (SAS)

AF:

0.00105

AC:

AN:

4752

European-Finnish (FIN)

AF:

0.0308

AC:

323

AN:

10470

Middle Eastern (MID)

AF:

0.00365

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.00966

AC:

653

AN:

67630

Other (OTH)

AF:

0.00430

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

126

188

251

314

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00891

Hom.:

Bravo

AF:

0.00687

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00676

EpiControl

AF:

0.00610

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Nov 20, 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. -

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.Pro1820Pro in exon 8 of ALMS1: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 2.93% (194/6614) of Finnish chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs62151609). -

Nov 19, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 27, 2019

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Mar 15, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ALMS1: BP4, BP7, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Alstrom syndrome

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 02, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

Cardiovascular phenotype

Benign:1

Feb 04, 2019

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

BayesDel_noAF

Benign

-0.90

CADD

Benign

5.7

(source)

DANN

Benign

0.65

PhyloP100

0.87

PromoterAI

0.0025

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(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