2-73385903-TGGAGGAGGAGGAGGAGGAGGAGGAGGA-TGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGA

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_001378454.1(ALMS1):c.66_74dupGGAGGAGGA(p.Glu23_Glu25dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E25E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0025 ( 2 hom., cov: 0)

Exomes 𝑓: 0.0039 ( 1 hom. )

Consequence

ALMS1
NM_001378454.1 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:12

Conservation

PhyloP100: 0.369

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 -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001378454.1

BP6

Variant 2-73385903-T-TGGAGGAGGA is Benign according to our data. Variant chr2-73385903-T-TGGAGGAGGA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193379.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00255 (366/143614) while in subpopulation SAS AF = 0.0136 (58/4258). AF 95% confidence interval is 0.0108. There are 2 homozygotes in GnomAd4. There are 182 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1 link	c.66_74dupGGAGGAGGA	p.Glu23_Glu25dup	disruptive_inframe_insertion	Exon 1 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 link	c.66_74dupGGAGGAGGA	p.Glu23_Glu25dup	disruptive_inframe_insertion	Exon 1 of 23		NP_055935.4	Q8TCU4
LOC105374804	XR_007087045.1 link	n.-231_-223dupTCCTCCTCC		upstream_gene_variant
LOC105374804	XR_007087053.1 link	n.-231_-223dupTCCTCCTCC		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 link	c.66_74dupGGAGGAGGA	p.Glu23_Glu25dup	disruptive_inframe_insertion	Exon 1 of 23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.00255

AC:

366

AN:

143510

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000778

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00450

Gnomad ASJ

AF:

0.00151

Gnomad EAS

AF:

0.00718

Gnomad SAS

AF:

0.0136

Gnomad FIN

AF:

0.00128

Gnomad MID

AF:

0.00355

Gnomad NFE

AF:

0.00239

Gnomad OTH

AF:

0.00307

GnomAD2 exomes

AF:

0.00428

AC:

357

AN:

83366

AF XY:

0.00456

show subpopulations

Gnomad AFR exome

AF:

0.000456

Gnomad AMR exome

AF:

0.00683

Gnomad ASJ exome

AF:

0.000937

Gnomad EAS exome

AF:

0.00666

Gnomad FIN exome

AF:

0.000717

Gnomad NFE exome

AF:

0.00108

Gnomad OTH exome

AF:

0.00325

GnomAD4 exome

AF:

0.00389

AC:

2169

AN:

557620

Hom.:

Cov.:

AF XY:

0.00433

AC XY:

1288

AN XY:

297754

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000570

AC:

AN:

15796

American (AMR)

AF:

0.00637

AC:

199

AN:

31224

Ashkenazi Jewish (ASJ)

AF:

0.00142

AC:

AN:

17646

East Asian (EAS)

AF:

0.0142

AC:

434

AN:

30624

South Asian (SAS)

AF:

0.0117

AC:

654

AN:

55908

European-Finnish (FIN)

AF:

0.00116

AC:

AN:

36320

Middle Eastern (MID)

AF:

0.00372

AC:

AN:

2422

European-Non Finnish (NFE)

AF:

0.00210

AC:

710

AN:

337560

Other (OTH)

AF:

0.00289

AC:

AN:

30120

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.376

Heterozygous variant carriers

109

219

328

438

547

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00255

AC:

366

AN:

143614

Hom.:

Cov.:

AF XY:

0.00261

AC XY:

182

AN XY:

69648

show subpopulations

African (AFR)

AF:

0.000776

AC:

AN:

39968

American (AMR)

AF:

0.00456

AC:

AN:

14696

Ashkenazi Jewish (ASJ)

AF:

0.00151

AC:

AN:

3322

East Asian (EAS)

AF:

0.00720

AC:

AN:

4582

South Asian (SAS)

AF:

0.0136

AC:

AN:

4258

European-Finnish (FIN)

AF:

0.00128

AC:

AN:

9398

Middle Eastern (MID)

AF:

0.00376

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.00238

AC:

153

AN:

64326

Other (OTH)

AF:

0.00304

AC:

AN:

1972

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

1022

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:6

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 27, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 16, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ALMS1: BS1 -

Alstrom syndrome

Uncertain:1Benign:3

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 11, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Oct 20, 2014

Eurofins Ntd Llc (ga)

Significance: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

- -

Cardiovascular phenotype

Benign:1

Nov 19, 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

PhyloP100

0.37

Mutation Taster

=78/22

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