Variant chr2-73385903-T-TGGAGGAGGA details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_001378454.1(ALMS1):c.66_74dup(p.Glu26_Glu28dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0025 ( 2 hom., cov: 0)

Exomes 𝑓: 0.0039 ( 1 hom. )

Consequence

ALMS1
NM_001378454.1 inframe_insertion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 0.369

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 193379.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=4}.

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 male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1 linkuse as main transcript	c.66_74dup	p.Glu26_Glu28dup	inframe_insertion	1/23	ENST00000613296.6
ALMS1	NM_015120.4 linkuse as main transcript	c.66_74dup	p.Glu26_Glu28dup	inframe_insertion	1/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6 linkuse as main transcript	c.66_74dup	p.Glu26_Glu28dup	inframe_insertion	1/23	1	NM_001378454.1	P3	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

GnomAD3 exomes

AF:

0.00428

AC:

357

AN:

83366

Hom.:

AF XY:

0.00456

AC XY:

199

AN XY:

43654

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 SAS exome

AF:

0.0106

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

Gnomad4 AFR exome

AF:

0.000570

Gnomad4 AMR exome

AF:

0.00637

Gnomad4 ASJ exome

AF:

0.00142

Gnomad4 EAS exome

AF:

0.0142

Gnomad4 SAS exome

AF:

0.0117

Gnomad4 FIN exome

AF:

0.00116

Gnomad4 NFE exome

AF:

0.00210

Gnomad4 OTH exome

AF:

0.00289

GnomAD4 genome

AF:

0.00255

AC:

366

AN:

143614

Hom.:

Cov.:

AF XY:

0.00261

AC XY:

182

AN XY:

69648

show subpopulations

Gnomad4 AFR

AF:

0.000776

Gnomad4 AMR

AF:

0.00456

Gnomad4 ASJ

AF:

0.00151

Gnomad4 EAS

AF:

0.00720

Gnomad4 SAS

AF:

0.0136

Gnomad4 FIN

AF:

0.00128

Gnomad4 NFE

AF:

0.00238

Gnomad4 OTH

AF:

0.00304

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

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 27, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ALMS1: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 16, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Alstrom syndrome

Uncertain:1Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 06, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Mar 05, 2018	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 20, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 19, 2018

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over