chr2-73385823-TC-T

Position:

• chr2-73385823-TC-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The ENST00000484298.5(ALMS1):​c.-39del variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00322 in 658,344 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (3 hom.)
• Consequence: ALMS1 ENST00000484298.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.98

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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00292 (424/145020) while in subpopulation NFE AF= 0.00505 (333/65924). AF 95% confidence interval is 0.0046. There are 1 homozygotes in gnomad4. There are 185 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALMS1	NM_015120.4	c.-39del		5_prime_UTR_variant	1/23		NP_055935.4
ALMS1	NM_001378454.1			upstream_gene_variant		ENST00000613296.6	NP_001365383.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000484298.5	c.-39del		5_prime_UTR_variant	1/22	1		ENSP00000478155	A2
ALMS1	ENST00000613296.6			upstream_gene_variant		1	NM_001378454.1	ENSP00000482968	P3
ALMS1	ENST00000614410.4			upstream_gene_variant		5		ENSP00000479094

Frequencies

GnomAD3 genomes AF: 0.00293 AC: 424 AN: 144946 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000668

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00117

Gnomad ASJ AF: 0.000293

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00294

Gnomad FIN AF: 0.00310

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00505

Gnomad OTH AF: 0.00201

GnomAD3 exomes AF: 0.00211 AC: 182 AN: 86338 Hom.: 0 AF XY: 0.00199 AC XY: 92 AN XY: 46172

Gnomad AFR exome AF: 0.000452

Gnomad AMR exome AF: 0.000959

Gnomad ASJ exome AF: 0.000211

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00191

Gnomad FIN exome AF: 0.00326

Gnomad NFE exome AF: 0.00380

Gnomad OTH exome AF: 0.00220

GnomAD4 exome AF: 0.00330 AC: 1695 AN: 513324 Hom.: 3 Cov.: 5 AF XY: 0.00331 AC XY: 913 AN XY: 276154

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.000945

Gnomad4 ASJ exome AF: 0.000173

Gnomad4 EAS exome AF: 0.0000327

Gnomad4 SAS exome AF: 0.00217

Gnomad4 FIN exome AF: 0.00310

Gnomad4 NFE exome AF: 0.00444

Gnomad4 OTH exome AF: 0.00265

GnomAD4 genome AF: 0.00292 AC: 424 AN: 145020 Hom.: 1 Cov.: 32 AF XY: 0.00263 AC XY: 185 AN XY: 70452

Gnomad4 AFR AF: 0.000666

Gnomad4 AMR AF: 0.00117

Gnomad4 ASJ AF: 0.000293

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00295

Gnomad4 FIN AF: 0.00310

Gnomad4 NFE AF: 0.00505

Gnomad4 OTH AF: 0.00199

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Alstrom syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs764473588; hg19: chr2-73612951;