2-73385903-TGGAGGAGGAGGAGGAGGAGGAGGAGGA-TGGAGGAGGAGGAGGAGGA

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_001378454.1(ALMS1):c.66_74delGGAGGAGGA(p.Glu23_Glu25del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 672,168 control chromosomes in the GnomAD database, including 48 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E22E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0066 ( 10 hom., cov: 0)

Exomes 𝑓: 0.015 ( 38 hom. )

Consequence

ALMS1
NM_001378454.1 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 3.45

Publications

7 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:

ENSG00000285068 (HGNC:):

ENSG00000285068 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001378454.1

BP6

Variant 2-73385903-TGGAGGAGGA-T is Benign according to our data. Variant chr2-73385903-TGGAGGAGGA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 403930.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 = 0.00658 (944/143536) while in subpopulation NFE AF = 0.0114 (731/64316). AF 95% confidence interval is 0.0107. There are 10 homozygotes in GnomAd4. There are 415 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1 link	c.66_74delGGAGGAGGA	p.Glu23_Glu25del	disruptive_inframe_deletion	Exon 1 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 link	c.66_74delGGAGGAGGA	p.Glu23_Glu25del	disruptive_inframe_deletion	Exon 1 of 23		NP_055935.4	Q8TCU4
LOC105374804	XR_007087045.1 link	n.-231_-223delTCCTCCTCC		upstream_gene_variant
LOC105374804	XR_007087053.1 link	n.-231_-223delTCCTCCTCC		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 link	c.66_74delGGAGGAGGA	p.Glu23_Glu25del	disruptive_inframe_deletion	Exon 1 of 23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.00658

AC:

944

AN:

143440

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00249

Gnomad AMI

AF:

0.00363

Gnomad AMR

AF:

0.00300

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00413

Gnomad SAS

AF:

0.00609

Gnomad FIN

AF:

0.000641

Gnomad MID

AF:

0.00355

Gnomad NFE

AF:

0.0114

Gnomad OTH

AF:

0.00768

GnomAD2 exomes

AF:

0.0196

AC:

1632

AN:

83366

AF XY:

0.0202

show subpopulations

Gnomad AFR exome

AF:

0.0488

Gnomad AMR exome

AF:

0.00969

Gnomad ASJ exome

AF:

0.0105

Gnomad EAS exome

AF:

0.0108

Gnomad FIN exome

AF:

0.0155

Gnomad NFE exome

AF:

0.0248

Gnomad OTH exome

AF:

0.0170

GnomAD4 exome

AF:

0.0146

AC:

7739

AN:

528632

Hom.:

AF XY:

0.0145

AC XY:

4082

AN XY:

282412

show subpopulations

African (AFR)

AF:

0.0318

AC:

409

AN:

12862

American (AMR)

AF:

0.00953

AC:

287

AN:

30126

Ashkenazi Jewish (ASJ)

AF:

0.00500

AC:

AN:

17004

East Asian (EAS)

AF:

0.00472

AC:

139

AN:

29472

South Asian (SAS)

AF:

0.0144

AC:

766

AN:

53104

European-Finnish (FIN)

AF:

0.00540

AC:

188

AN:

34834

Middle Eastern (MID)

AF:

0.00694

AC:

AN:

2304

European-Non Finnish (NFE)

AF:

0.0170

AC:

5447

AN:

320622

Other (OTH)

AF:

0.0142

AC:

402

AN:

28304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.420

Heterozygous variant carriers

316

631

947

1262

1578

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

192

288

384

480

<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:

0.00658

AC:

944

AN:

143536

Hom.:

Cov.:

AF XY:

0.00596

AC XY:

415

AN XY:

69596

show subpopulations

African (AFR)

AF:

0.00248

AC:

AN:

39936

American (AMR)

AF:

0.00299

AC:

AN:

14694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3322

East Asian (EAS)

AF:

0.00414

AC:

AN:

4584

South Asian (SAS)

AF:

0.00610

AC:

AN:

4264

European-Finnish (FIN)

AF:

0.000641

AC:

AN:

9356

Middle Eastern (MID)

AF:

0.00376

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.0114

AC:

731

AN:

64316

Other (OTH)

AF:

0.00761

AC:

AN:

1972

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.527

Heterozygous variant carriers

122

163

204

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:

0.0140

Hom.:

1022

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 15, 2017

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 27, 2017

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

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

Significance:Likely benign

Review Status:no assertion criteria provided

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

- -

Mar 27, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Alstrom syndrome

Benign:2

Nov 05, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

Cardiovascular phenotype

Benign:1

Oct 11, 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

PhyloP100

3.4

Mutation Taster

=198/2

polymorphism

(source)

Splicing

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