2-73385903-T-TGGAGGAGGA

Position:

• chr2-73385903-T-TGGAGGAGGA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP3 BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 0.369

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]

ACMG classification

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	c.66_74dup	p.Glu26_Glu28dup	inframe_insertion	1/23	ENST00000613296.6
ALMS1	NM_015120.4	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	c.66_74dup	p.Glu26_Glu28dup	inframe_insertion	1/23	1	NM_001378454.1	P3

Frequencies

GnomAD3 genomes AF: 0.00255 AC: 366 AN: 143510 Hom.: 2 Cov.: 0

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.: 4 AF XY: 0.00456 AC XY: 199 AN XY: 43654

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.: 1 Cov.: 0 AF XY: 0.00433 AC XY: 1288 AN XY: 297754

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.: 2 Cov.: 0 AF XY: 0.00261 AC XY: 182 AN XY: 69648

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:1 Benign:12

Revision: criteria provided, conflicting classifications

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:1 Benign: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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs55889738; hg19: chr2-73613031;