2-73385903-TGGA-T

Position:

• chr2-73385903-TGGA-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_001378454.1(ALMS1):​c.72_74del​(p.Glu28del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0385 in 698,502 control chromosomes in the GnomAD database, including 613 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (348 hom., cov: 0)
  • Exomes 𝑓: 0.034 (265 hom.)
• Consequence: ALMS1 NM_001378454.1 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 3.18

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 -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001378454.1
• BP6: Variant 2-73385903-TGGA-T is Benign according to our data. Variant chr2-73385903-TGGA-T is described in ClinVar as [Likely_benign]. Clinvar id is 193378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALMS1	NM_001378454.1	c.72_74del	p.Glu28del	inframe_deletion	1/23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4	c.72_74del	p.Glu29del	inframe_deletion	1/23		NP_055935.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6	c.72_74del	p.Glu28del	inframe_deletion	1/23	1	NM_001378454.1	ENSP00000482968	P3

Frequencies

GnomAD3 genomes AF: 0.0546 AC: 7831 AN: 143476 Hom.: 344 Cov.: 0

Gnomad AFR AF: 0.0949

Gnomad AMI AF: 0.0170

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.0316

Gnomad EAS AF: 0.0424

Gnomad SAS AF: 0.0136

Gnomad FIN AF: 0.0458

Gnomad MID AF: 0.0142

Gnomad NFE AF: 0.0233

Gnomad OTH AF: 0.0450

GnomAD3 exomes AF: 0.0631 AC: 5258 AN: 83366 Hom.: 225 AF XY: 0.0545 AC XY: 2380 AN XY: 43654

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.172

Gnomad ASJ exome AF: 0.0365

Gnomad EAS exome AF: 0.0407

Gnomad SAS exome AF: 0.0114

Gnomad FIN exome AF: 0.0392

Gnomad NFE exome AF: 0.0252

Gnomad OTH exome AF: 0.0560

GnomAD4 exome AF: 0.0343 AC: 19023 AN: 554922 Hom.: 265 AF XY: 0.0323 AC XY: 9565 AN XY: 296246

Gnomad4 AFR exome AF: 0.0885

Gnomad4 AMR exome AF: 0.155

Gnomad4 ASJ exome AF: 0.0327

Gnomad4 EAS exome AF: 0.0352

Gnomad4 SAS exome AF: 0.0127

Gnomad4 FIN exome AF: 0.0403

Gnomad4 NFE exome AF: 0.0234

Gnomad4 OTH exome AF: 0.0371

GnomAD4 genome AF: 0.0547 AC: 7850 AN: 143580 Hom.: 348 Cov.: 0 AF XY: 0.0555 AC XY: 3865 AN XY: 69632

Gnomad4 AFR AF: 0.0949

Gnomad4 AMR AF: 0.114

Gnomad4 ASJ AF: 0.0316

Gnomad4 EAS AF: 0.0423

Gnomad4 SAS AF: 0.0134

Gnomad4 FIN AF: 0.0458

Gnomad4 NFE AF: 0.0233

Gnomad4 OTH AF: 0.0456

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 12, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 18, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Feb 11, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 05, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 04, 2013	- -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Alstrom syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Jul 07, 2023	- -

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

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

LitVar

Other links and lift over

dbSNP: rs55889738; hg19: chr2-73613031;