2-73385821-C-T

Variant names:

• chr2-73385821-C-T
• rs543687863
• ENST00000484298.5:c.-48C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_015120.4(ALMS1):​c.-48C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000494 in 680,838 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00058 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (1 hom.)
• Consequence: ALMS1 NM_015120.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.134
• 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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000578 (88/152130) while in subpopulation AMR AF = 0.000915 (14/15300). AF 95% confidence interval is 0.000678. There are 1 homozygotes in GnomAd4. There are 36 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_015120.4	c.-48C>T		5_prime_UTR_variant	Exon 1 of 23		NP_055935.4
ALMS1	NM_001378454.1	c.-48C>T		upstream_gene_variant		ENST00000613296.6	NP_001365383.1
LOC105374804	XR_007087045.1	n.-140G>A		upstream_gene_variant
LOC105374804	XR_007087053.1	n.-140G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6	c.-48C>T		upstream_gene_variant		1	NM_001378454.1	ENSP00000482968.1

Frequencies

GnomAD3 genomes AF: 0.000579 AC: 88 AN: 152026 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000854

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000386 AC: 39 AN: 100932 AF XY: 0.000261

Gnomad AFR exome AF: 0.000402

Gnomad AMR exome AF: 0.000184

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000895

Gnomad OTH exome AF: 0.000306

GnomAD4 exome AF: 0.000469 AC: 248 AN: 528708 Hom.: 1 Cov.: 5 AF XY: 0.000478 AC XY: 136 AN XY: 284468

African (AFR) AF: 0.000335 AC: 5 AN: 14928

American (AMR) AF: 0.000246 AC: 8 AN: 32466

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18062

East Asian (EAS) AF: 0.00 AC: 0 AN: 31324

South Asian (SAS) AF: 0.00 AC: 0 AN: 56466

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33752

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2358

European-Non Finnish (NFE) AF: 0.000714 AC: 221 AN: 309698

Other (OTH) AF: 0.000472 AC: 14 AN: 29654

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152130 Hom.: 1 Cov.: 32 AF XY: 0.000484 AC XY: 36 AN XY: 74374

African (AFR) AF: 0.000265 AC: 11 AN: 41554

American (AMR) AF: 0.000915 AC: 14 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000854 AC: 58 AN: 67928

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.0000856 Hom.: 0

Bravo AF: 0.000586

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Alstrom syndrome Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	11
DANN	Benign	0.73
PhyloP100		0.13
PromoterAI		0.031	Neutral
Mutation Taster		=300/0	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: rs543687863; hg19: chr2-73612949;