rs35760114

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001378454.1(ALMS1):c.11523G>A(p.Glu3841Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00373 in 1,614,028 control chromosomes in the GnomAD database, including 178 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 112 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 66 hom. )

Consequence

ALMS1
NM_001378454.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.393

Publications

1 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=-0.52).

BP6

Variant 2-73573400-G-A is Benign according to our data. Variant chr2-73573400-G-A is described in ClinVar as Benign. ClinVar VariationId is 220881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.393 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.063 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1 link	c.11523G>A	p.Glu3841Glu	synonymous_variant	Exon 16 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 link	c.11523G>A	p.Glu3841Glu	synonymous_variant	Exon 16 of 23		NP_055935.4	Q8TCU4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 link	c.11523G>A	p.Glu3841Glu	synonymous_variant	Exon 16 of 23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.0193

AC:

2941

AN:

152174

Hom.:

112

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0107

Gnomad ASJ

AF:

0.00836

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.00861

GnomAD2 exomes

AF:

0.00505

AC:

1257

AN:

248794

AF XY:

0.00380

show subpopulations

Gnomad AFR exome

AF:

0.0640

Gnomad AMR exome

AF:

0.00372

Gnomad ASJ exome

AF:

0.00906

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000266

Gnomad OTH exome

AF:

0.00282

GnomAD4 exome

AF:

0.00211

AC:

3079

AN:

1461736

Hom.:

Cov.:

AF XY:

0.00186

AC XY:

1356

AN XY:

727156

show subpopulations

African (AFR)

AF:

0.0628

AC:

2103

AN:

33478

American (AMR)

AF:

0.00434

AC:

194

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.00876

AC:

229

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.0000928

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00312

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000210

AC:

233

AN:

1111970

Other (OTH)

AF:

0.00487

AC:

294

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

199

398

597

796

995

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.0193

AC:

2946

AN:

152292

Hom.:

112

Cov.:

AF XY:

0.0191

AC XY:

1420

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0651

AC:

2704

AN:

41556

American (AMR)

AF:

0.0107

AC:

163

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00836

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000426

AC:

AN:

68018

Other (OTH)

AF:

0.00852

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

130

260

389

519

649

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:

0.00940

Hom.:

Bravo

AF:

0.0220

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Oct 12, 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. -

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.Glu3840Glu in exon 16 of ALMS1: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 6.48% (622/9602) o f African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs35760114). -

Feb 15, 2016

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ALMS1 c.11520G>A (alternative name c.11526G>A) affects a non-conserved nucleotide, resulting in a synonymous change. 3/5 programs in Alamut predict that this variant does not affect normal splicing. This variant was found in 723/118816 control chromosomes at a frequency of 0.006085, predominantly observed in African subpopulation in ExAC with MAF of 0.06478 with 21 homozygotes. This frequency exceeds the maximal expected frequency of a pathogenic allele (0.0022361), suggesting this variant is benign especially for Africans. This variant, to our knowledge, has not been reported in affected individuals via publications. One clinical laboratory (via ClinVar) classified this variant as benign, without evidence to independently evaluate. Taken together, this variant was classified as benign. -

Alstrom syndrome

Benign:3

Nov 12, 2024

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

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 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

BayesDel_noAF

Benign

-0.52

CADD

Benign

2.9

(source)

DANN

Benign

0.57

PhyloP100

0.39

Mutation Taster

=98/2

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