2-73385903-T-TGGAGGAGGAGGA

Position:

• chr2-73385903-T-TGGAGGAGGAGGA

Variant summary

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

The NM_001378454.1(ALMS1):​c.63_74dup​(p.Glu25_Glu28dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0025 (2 hom.)
• Consequence: ALMS1 NM_001378454.1 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications 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 -10 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001378454.1
• BP6: Variant 2-73385903-T-TGGAGGAGGAGGA is Benign according to our data. Variant chr2-73385903-T-TGGAGGAGGAGGA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 412658.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00126 (181/143630) while in subpopulation EAS AF= 0.0236 (108/4582). AF 95% confidence interval is 0.02. There are 1 homozygotes in gnomad4. There are 101 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1	c.63_74dup	p.Glu25_Glu28dup	inframe_insertion	1/23	ENST00000613296.6
ALMS1	NM_015120.4	c.63_74dup	p.Glu25_Glu28dup	inframe_insertion	1/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6	c.63_74dup	p.Glu25_Glu28dup	inframe_insertion	1/23	1	NM_001378454.1	P3

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 183 AN: 143526 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.000151

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000817

Gnomad ASJ AF: 0.000301

Gnomad EAS AF: 0.0235

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.000106

Gnomad MID AF: 0.00355

Gnomad NFE AF: 0.000606

Gnomad OTH AF: 0.00358

GnomAD4 exome AF: 0.00250 AC: 1392 AN: 557702 Hom.: 2 Cov.: 0 AF XY: 0.00239 AC XY: 711 AN XY: 297806

Gnomad4 AFR exome AF: 0.000127

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.00130

Gnomad4 EAS exome AF: 0.0364

Gnomad4 SAS exome AF: 0.000644

Gnomad4 FIN exome AF: 0.000193

Gnomad4 NFE exome AF: 0.000353

Gnomad4 OTH exome AF: 0.00166

GnomAD4 genome AF: 0.00126 AC: 181 AN: 143630 Hom.: 1 Cov.: 0 AF XY: 0.00145 AC XY: 101 AN XY: 69660

Gnomad4 AFR AF: 0.000150

Gnomad4 AMR AF: 0.000816

Gnomad4 ASJ AF: 0.000301

Gnomad4 EAS AF: 0.0236

Gnomad4 SAS AF: 0.00164

Gnomad4 FIN AF: 0.000106

Gnomad4 NFE AF: 0.000606

Gnomad4 OTH AF: 0.00304

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Alstrom syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Nov 25, 2019

Variant summary: The ALMS1 variant, c.66_74dupGGAGGAGGA (p.Glu26_Glu28dup, also known as c.69_77dup) is located in a Glu repetitive region. The variant allele was found at a frequency of 0.0043 in 83366 control chromosomes, predominantly at a frequency of 0.011 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 5-folds over the estimated maximal expected allele frequency for a pathogenic variant in ALMS1 causing Cardiomyopathy phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.66_74dupGGAGGAGGA in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. 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 benign. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 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;