chr2-73385903-TGGAGGAGGAGGAGGA-T

Variant names:

• chr2-73385903-TGGAGGAGGAGGAGGA-T
• rs55889738
• NM_001378454.1:c.60_74delGGAGGAGGAGGAGGA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP3 BP6 BS1 BS2

The NM_001378454.1(ALMS1):​c.60_74delGGAGGAGGAGGAGGA​(p.Glu21_Glu25del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 557,738 control chromosomes in the GnomAD database, including 17 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.012 (35 hom., cov: 0)
  • Exomes 𝑓: 0.0017 (17 hom.)
  • Failed GnomAD Quality Control
• Consequence: ALMS1 NM_001378454.1 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• 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]

ENSG00000285068 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001378454.1
• BP6: Variant 2-73385903-TGGAGGAGGAGGAGGA-T is Benign according to our data. Variant chr2-73385903-TGGAGGAGGAGGAGGA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241004.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.00173 (963/557738) while in subpopulation AFR AF= 0.04 (632/15792). AF 95% confidence interval is 0.0374. There are 17 homozygotes in gnomad4_exome. There are 417 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1	c.60_74delGGAGGAGGAGGAGGA	p.Glu21_Glu25del	disruptive_inframe_deletion	Exon 1 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4	c.60_74delGGAGGAGGAGGAGGA	p.Glu21_Glu25del	disruptive_inframe_deletion	Exon 1 of 23		NP_055935.4
LOC105374804	XR_007087045.1	n.-237_-223delTCCTCCTCCTCCTCC		upstream_gene_variant
LOC105374804	XR_007087053.1	n.-237_-223delTCCTCCTCCTCCTCC		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6	c.60_74delGGAGGAGGAGGAGGA	p.Glu21_Glu25del	disruptive_inframe_deletion	Exon 1 of 23	1	NM_001378454.1	ENSP00000482968.1

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1737 AN: 143526 Hom.: 35 Cov.: 0

Gnomad AFR AF: 0.0394

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00783

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000870

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000106

Gnomad MID AF: 0.00709

Gnomad NFE AF: 0.000264

Gnomad OTH AF: 0.0138

GnomAD4 exome AF: 0.00173 AC: 963 AN: 557738 Hom.: 17 AF XY: 0.00140 AC XY: 417 AN XY: 297826

Gnomad4 AFR exome AF: 0.0400

Gnomad4 AMR exome AF: 0.00365

Gnomad4 ASJ exome AF: 0.0000567

Gnomad4 EAS exome AF: 0.000326

Gnomad4 SAS exome AF: 0.0000536

Gnomad4 FIN exome AF: 0.0000826

Gnomad4 NFE exome AF: 0.000213

Gnomad4 OTH exome AF: 0.00392

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0121 AC: 1740 AN: 143630 Hom.: 35 Cov.: 0 AF XY: 0.0119 AC XY: 830 AN XY: 69660

Gnomad4 AFR AF: 0.0394

Gnomad4 AMR AF: 0.00782

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000873

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000106

Gnomad4 NFE AF: 0.000264

Gnomad4 OTH AF: 0.0137

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

May 17, 2021

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ALMS1 c.57_74del18 (p.Glu23_Glu28del) results in an in-frame deletion that is predicted to remove six amino acids from the repeat region of 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_74del18 in individuals affected with Alstrom Syndrome With Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One co-occurrence with another pathogenic variant has been reported internally (MYBPC3 c.1227-13G>A), providing supporting evidence for a benign role. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Benign:1

Mar 03, 2022

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

May 15, 2020

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;