chr2-73385903-T-TGGAGGAGGAGGAGGAGGA

Position:

• chr2-73385903-T-TGGAGGAGGAGGAGGAGGA

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP3 BP6_Very_Strong BS1

The NM_001378454.1(ALMS1):​c.57_74dup​(p.Glu23_Glu28dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: ALMS1 NM_001378454.1 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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 -13 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001378454.1
• BP6: Variant 2-73385903-T-TGGAGGAGGAGGAGGAGGA is Benign according to our data. Variant chr2-73385903-T-TGGAGGAGGAGGAGGAGGA is described in ClinVar as [Likely_benign]. Clinvar id is 459877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000312 (174/557704) while in subpopulation EAS AF= 0.00124 (38/30670). AF 95% confidence interval is 0.000928. There are 0 homozygotes in gnomad4_exome. There are 89 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1	c.57_74dup	p.Glu23_Glu28dup	inframe_insertion	1/23	ENST00000613296.6
ALMS1	NM_015120.4	c.57_74dup	p.Glu23_Glu28dup	inframe_insertion	1/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6	c.57_74dup	p.Glu23_Glu28dup	inframe_insertion	1/23	1	NM_001378454.1	P3

Frequencies

GnomAD3 genomes AF: 0.000286 AC: 41 AN: 143522 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000100

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000681

Gnomad ASJ AF: 0.00151

Gnomad EAS AF: 0.00131

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000373

Gnomad OTH AF: 0.000512

GnomAD4 exome AF: 0.000312 AC: 174 AN: 557704 Hom.: 0 Cov.: 0 AF XY: 0.000299 AC XY: 89 AN XY: 297814

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000640

Gnomad4 ASJ exome AF: 0.00102

Gnomad4 EAS exome AF: 0.00124

Gnomad4 SAS exome AF: 0.000143

Gnomad4 FIN exome AF: 0.0000275

Gnomad4 NFE exome AF: 0.000290

Gnomad4 OTH exome AF: 0.000299

GnomAD4 genome AF: 0.000285 AC: 41 AN: 143626 Hom.: 0 Cov.: 0 AF XY: 0.000215 AC XY: 15 AN XY: 69658

Gnomad4 AFR AF: 0.000100

Gnomad4 AMR AF: 0.0000680

Gnomad4 ASJ AF: 0.00151

Gnomad4 EAS AF: 0.00131

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000373

Gnomad4 OTH AF: 0.000507

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 02, 2020	Variant summary: The variant in ALMS1, c.60_74dup15 (p.Glu24_Glu28dup) results in an in-frame duplication in a Glu repetitive region of the ALMS1 protein (Glu13_Glu28). The variant was absent in 83366 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.60_74dup15 in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Furthermore, there are no reports of other variants in this Glu repetitive region in the HGMD database. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Oher duplication variants located in this Glu repetitive region (examples: p.Glu26_Glu28dup, p.Glu23_Glu24dup, p.Glu24dup) have been classified as benign by our laboratory. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 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;