2-73385823-TC-T

Variant names:

• chr2-73385823-TC-T
• rs764473588
• ENST00000484298.5:c.-39delC

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_015120.4(ALMS1):​c.-39delC 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 NM_015120.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.98
• Publications: 0 publications found

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]

ALMS1 Gene-Disease associations (from GenCC):

• Alstrom syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Orphanet, Genomics England PanelApp

ENSG00000285068 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. 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 rank	MANE	Protein	UniProt
ALMS1	NM_015120.4	c.-39delC		5_prime_UTR_variant	Exon 1 of 23		NP_055935.4
ALMS1	NM_001378454.1	c.-45delC		upstream_gene_variant		ENST00000613296.6	NP_001365383.1
LOC105374804	XR_007087045.1	n.-143delG		upstream_gene_variant
LOC105374804	XR_007087053.1	n.-143delG		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6	c.-45delC		upstream_gene_variant		1	NM_001378454.1	ENSP00000482968.1

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

GnomAD2 exomes AF: 0.00211 AC: 182 AN: 86338 AF XY: 0.00199

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 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

African (AFR) AF: 0.00120 AC: 17 AN: 14118

American (AMR) AF: 0.000945 AC: 28 AN: 29626

Ashkenazi Jewish (ASJ) AF: 0.000173 AC: 3 AN: 17328

East Asian (EAS) AF: 0.0000327 AC: 1 AN: 30606

South Asian (SAS) AF: 0.00217 AC: 120 AN: 55338

European-Finnish (FIN) AF: 0.00310 AC: 103 AN: 33274

Middle Eastern (MID) AF: 0.00220 AC: 5 AN: 2268

European-Non Finnish (NFE) AF: 0.00444 AC: 1342 AN: 302116

Other (OTH) AF: 0.00265 AC: 76 AN: 28650

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

African (AFR) AF: 0.000666 AC: 26 AN: 39026

American (AMR) AF: 0.00117 AC: 17 AN: 14592

Ashkenazi Jewish (ASJ) AF: 0.000293 AC: 1 AN: 3408

East Asian (EAS) AF: 0.00 AC: 0 AN: 4818

South Asian (SAS) AF: 0.00295 AC: 13 AN: 4412

European-Finnish (FIN) AF: 0.00310 AC: 30 AN: 9670

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.00505 AC: 333 AN: 65924

Other (OTH) AF: 0.00199 AC: 4 AN: 2008

Alfa AF: 0.00204 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Alstrom syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.0
Mutation Taster		=298/2	polymorphism

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

Other links and lift over

dbSNP: rs764473588; hg19: chr2-73612951;