chr2-73385903-TGGAGGAGGA-T

Position:

• chr2-73385903-TGGAGGAGGA-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_001378454.1(ALMS1):​c.66_74del​(p.Glu26_Glu28del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 672,168 control chromosomes in the GnomAD database, including 48 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (10 hom., cov: 0)
  • Exomes 𝑓: 0.015 (38 hom.)
• Consequence: ALMS1 NM_001378454.1 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 3.45

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-TGGAGGAGGA-T is Benign according to our data. Variant chr2-73385903-TGGAGGAGGA-T is described in ClinVar as [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALMS1	NM_001378454.1	c.66_74del	p.Glu26_Glu28del	inframe_deletion	1/23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4	c.66_74del	p.Glu27_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.66_74del	p.Glu26_Glu28del	inframe_deletion	1/23	1	NM_001378454.1	ENSP00000482968	P3

Frequencies

GnomAD3 genomes AF: 0.00658 AC: 944 AN: 143440 Hom.: 10 Cov.: 0

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

GnomAD3 exomes AF: 0.0196 AC: 1632 AN: 83366 Hom.: 13 AF XY: 0.0202 AC XY: 880 AN XY: 43654

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 SAS exome AF: 0.0217

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.: 38 AF XY: 0.0145 AC XY: 4082 AN XY: 282412

Gnomad4 AFR exome AF: 0.0318

Gnomad4 AMR exome AF: 0.00953

Gnomad4 ASJ exome AF: 0.00500

Gnomad4 EAS exome AF: 0.00472

Gnomad4 SAS exome AF: 0.0144

Gnomad4 FIN exome AF: 0.00540

Gnomad4 NFE exome AF: 0.0170

Gnomad4 OTH exome AF: 0.0142

GnomAD4 genome AF: 0.00658 AC: 944 AN: 143536 Hom.: 10 Cov.: 0 AF XY: 0.00596 AC XY: 415 AN XY: 69596

Gnomad4 AFR AF: 0.00248

Gnomad4 AMR AF: 0.00299

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00414

Gnomad4 SAS AF: 0.00610

Gnomad4 FIN AF: 0.000641

Gnomad4 NFE AF: 0.0114

Gnomad4 OTH AF: 0.00761

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 27, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 15, 2017	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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	Mar 27, 2017	- -

Alstrom syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 11, 2019

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;