2-73385903-TGGAGGA-T

Position:

• chr2-73385903-TGGAGGA-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.69_74del​(p.Glu27_Glu28del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 700,128 control chromosomes in the GnomAD database, including 21,830 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12811 hom., cov: 0)
  • Exomes 𝑓: 0.27 (9019 hom.)
• Consequence: ALMS1 NM_001378454.1 inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.21

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-TGGAGGA-T is Benign according to our data. Variant chr2-73385903-TGGAGGA-T is described in ClinVar as [Benign]. Clinvar id is 221075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.642 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1	c.69_74del	p.Glu27_Glu28del	inframe_deletion	1/23	ENST00000613296.6
ALMS1	NM_015120.4	c.69_74del	p.Glu28_Glu29del	inframe_deletion	1/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6	c.69_74del	p.Glu27_Glu28del	inframe_deletion	1/23	1	NM_001378454.1	P3

Frequencies

GnomAD3 genomes AF: 0.394 AC: 56506 AN: 143428 Hom.: 12779 Cov.: 0

Gnomad AFR AF: 0.648

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.308

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.205

Gnomad SAS AF: 0.284

Gnomad FIN AF: 0.272

Gnomad MID AF: 0.254

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.354

GnomAD3 exomes AF: 0.286 AC: 23877 AN: 83366 Hom.: 2813 AF XY: 0.281 AC XY: 12288 AN XY: 43654

Gnomad AFR exome AF: 0.613

Gnomad AMR exome AF: 0.247

Gnomad ASJ exome AF: 0.265

Gnomad EAS exome AF: 0.194

Gnomad SAS exome AF: 0.259

Gnomad FIN exome AF: 0.304

Gnomad NFE exome AF: 0.300

Gnomad OTH exome AF: 0.271

GnomAD4 exome AF: 0.268 AC: 148993 AN: 556596 Hom.: 9019 AF XY: 0.265 AC XY: 78880 AN XY: 297226

Gnomad4 AFR exome AF: 0.514

Gnomad4 AMR exome AF: 0.246

Gnomad4 ASJ exome AF: 0.233

Gnomad4 EAS exome AF: 0.213

Gnomad4 SAS exome AF: 0.245

Gnomad4 FIN exome AF: 0.245

Gnomad4 NFE exome AF: 0.271

Gnomad4 OTH exome AF: 0.270

GnomAD4 genome AF: 0.394 AC: 56594 AN: 143532 Hom.: 12811 Cov.: 0 AF XY: 0.389 AC XY: 27093 AN XY: 69610

Gnomad4 AFR AF: 0.648

Gnomad4 AMR AF: 0.308

Gnomad4 ASJ AF: 0.272

Gnomad4 EAS AF: 0.204

Gnomad4 SAS AF: 0.284

Gnomad4 FIN AF: 0.272

Gnomad4 NFE AF: 0.304

Gnomad4 OTH AF: 0.353

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 04, 2018	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Alstrom syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Jun 06, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2016	This variant is associated with the following publications: (PMID: 24122612, 25468891) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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;