2-73385958-AGCGGCG-AGCGGCGGCG

Variant names:

• chr2-73385958-A-AGCG
• rs746896173
• NM_001378454.1:c.103_105dupGCG

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_001378454.1(ALMS1):​c.103_105dupGCG​(p.Ala35dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,399,048 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: ALMS1 NM_001378454.1 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 0.260

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001378454.1. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1	c.103_105dupGCG	p.Ala35dup	conservative_inframe_insertion	Exon 1 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4	c.103_105dupGCG	p.Ala35dup	conservative_inframe_insertion	Exon 1 of 23		NP_055935.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6	c.103_105dupGCG	p.Ala35dup	conservative_inframe_insertion	Exon 1 of 23	1	NM_001378454.1	ENSP00000482968.1

Frequencies

GnomAD3 genomes AF: 0.000119 AC: 18 AN: 150814 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000594

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000201

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000191

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000592

Gnomad OTH AF: 0.000482

GnomAD3 exomes AF: 0.000144 AC: 20 AN: 139126 Hom.: 0 AF XY: 0.000122 AC XY: 9 AN XY: 73674

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000475

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000102

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000276

Gnomad NFE exome AF: 0.0000753

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000117 AC: 146 AN: 1248124 Hom.: 0 Cov.: 19 AF XY: 0.000122 AC XY: 76 AN XY: 622360

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000428

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000291

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000144

Gnomad4 NFE exome AF: 0.000122

Gnomad4 OTH exome AF: 0.000151

GnomAD4 genome AF: 0.000119 AC: 18 AN: 150924 Hom.: 0 Cov.: 32 AF XY: 0.000163 AC XY: 12 AN XY: 73692

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.000593

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000202

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000191

Gnomad4 NFE AF: 0.0000592

Gnomad4 OTH AF: 0.000476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Alstrom syndrome Uncertain:4

Mar 14, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.106_108dup, results in the insertion of 1 amino acid(s) of the ALMS1 protein (p.Ala36dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs746896173, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with ALMS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 337007). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 28, 2021

Clinical Genomics Laboratory, Stanford Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ala36dup variant in the ALMS1gene has not been previously reported in association with disease. This p.Ala36dup varianthas been identified in 11/23,978 Latino/Admixed American chromosomes (22/170,160 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/).The p.Ala36dup variant occurs in a repetitive region and the ability to detect this type of variation is limited. Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The p.Ala36dupvariant results in an in-frame insertion of oneamino acid, and as a result, this variant is not expected to disrupt the protein reading frame. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of thep.Ala36dupvariant is uncertain. Additional information is needed to resolve the significance of this variant.[ACMG evidence codes used: BP3] -

ALMS1-related disorder Uncertain:1

Jun 10, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ALMS1 c.103_105dupGCG variant is predicted to result in an in-frame duplication (p.Ala35dup). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.046% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype Uncertain:1

Aug 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.106_108dupGCG variant (also known as p.A36dup), located in coding exon 1 of the ALMS1 gene, results from an in-frame duplication of GCG at nucleotide positions 106 to 108. This results in the duplication of an extra alanine residue between codons 36 and 37. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Apr 07, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: rs746896173; hg19: chr2-73613086;