3-184242362-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_005787.6(ALG3):c.*152C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000318 in 955,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: ALG3 NM_005787.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.366

Genes affected

ALG3 (HGNC:23056): (ALG3 alpha-1,3- mannosyltransferase) This gene encodes a member of the ALG3 family. The encoded protein catalyses the addition of the first dol-P-Man derived mannose in an alpha 1,3 linkage to Man5GlcNAc2-PP-Dol. Defects in this gene have been associated with congenital disorder of glycosylation type Id (CDG-Id) characterized by abnormal N-glycosylation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2008]

VWA5B2 (HGNC:25144): (von Willebrand factor A domain containing 5B2)

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000256 (39/152162) while in subpopulation EAS AF= 0.0033 (17/5156). AF 95% confidence interval is 0.0021. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALG3	NM_005787.6	c.*152C>T		3_prime_UTR_variant	9/9	ENST00000397676.8
VWA5B2	NM_001390846.1			downstream_gene_variant		ENST00000691901.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG3	ENST00000397676.8	c.*152C>T		3_prime_UTR_variant	9/9	1	NM_005787.6	P1
VWA5B2	ENST00000691901.1			downstream_gene_variant			NM_001390846.1	P1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152044 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00348

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000630 AC: 95 AN: 150832 Hom.: 0 AF XY: 0.000650 AC XY: 52 AN XY: 80050

Gnomad AFR exome AF: 0.000255

Gnomad AMR exome AF: 0.000324

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00521

Gnomad SAS exome AF: 0.000264

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000320

Gnomad OTH exome AF: 0.000693

GnomAD4 exome AF: 0.000330 AC: 265 AN: 803420 Hom.: 0 Cov.: 11 AF XY: 0.000347 AC XY: 145 AN XY: 417846

Gnomad4 AFR exome AF: 0.000395

Gnomad4 AMR exome AF: 0.000372

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00305

Gnomad4 SAS exome AF: 0.000120

Gnomad4 FIN exome AF: 0.0000227

Gnomad4 NFE exome AF: 0.000181

Gnomad4 OTH exome AF: 0.000519

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152162 Hom.: 0 Cov.: 33 AF XY: 0.000229 AC XY: 17 AN XY: 74370

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00330

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000384 Hom.: 0

Bravo AF: 0.000544

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

ALG3-congenital disorder of glycosylation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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	-0.93
Cadd	Benign	0.89
Dann	Benign	0.45

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: rs186599528; hg19: chr3-183960150;