2-73385903-T-TGGAGGAGGAGGAGGAGGAGGA

Position:

• chr2-73385903-T-TGGAGGAGGAGGAGGAGGAGGA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP3 BP6_Very_Strong

The NM_001378454.1(ALMS1):​c.54_74dup​(p.Glu22_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 0.000084 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000074 (0 hom.)
• Consequence: ALMS1 NM_001378454.1 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:2
• 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 -9 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001378454.1
• BP6: Variant 2-73385903-T-TGGAGGAGGAGGAGGAGGAGGA is Benign according to our data. Variant chr2-73385903-T-TGGAGGAGGAGGAGGAGGAGGA is described in ClinVar as [Likely_benign]. Clinvar id is 241005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1	c.54_74dup	p.Glu22_Glu28dup	inframe_insertion	1/23	ENST00000613296.6
ALMS1	NM_015120.4	c.54_74dup	p.Glu22_Glu28dup	inframe_insertion	1/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6	c.54_74dup	p.Glu22_Glu28dup	inframe_insertion	1/23	1	NM_001378454.1	P3

Frequencies

GnomAD3 genomes AF: 0.0000836 AC: 12 AN: 143532 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000681

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000870

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000213

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000622

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000735 AC: 41 AN: 557726 Hom.: 0 Cov.: 0 AF XY: 0.0000638 AC XY: 19 AN XY: 297820

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000567

Gnomad4 EAS exome AF: 0.000294

Gnomad4 SAS exome AF: 0.0000358

Gnomad4 FIN exome AF: 0.000110

Gnomad4 NFE exome AF: 0.0000711

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000835 AC: 12 AN: 143636 Hom.: 0 Cov.: 0 AF XY: 0.0000718 AC XY: 5 AN XY: 69662

Gnomad4 AFR AF: 0.0000250

Gnomad4 AMR AF: 0.0000680

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000873

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000213

Gnomad4 NFE AF: 0.0000622

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alstrom syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 01, 2019

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 07, 2023

Variant summary: ALMS1 c.57_74dup18 (p.Glu23_Glu28dup) results in an in-frame duplication that is predicted to duplicate 6 amino acids into the ALMS repeat region/Glu repetitive region (Glu13_Glu28) of the encoded protein. 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.57_74dup18 in individuals affected with Alstrom Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Other duplication variants located in this Glu repetitive region (examples: c.54_74dup21/p.Glu22_Glu28dup, c.60_74dup15/p.Glu24_Glu28dup) have been classified as likely benign by our laboratory. Furthermore, there are no reports of other variants in this Glu repetitive region in the HGMD database. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as benign. Based on the evidence outlined above, the variant was classified as as likely benign. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 18, 2021

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;