rs706584

Variant names:

• chr3-184242464-A-C
• rs706584
• ENST00000411922.5:n.*943T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000411922.5(ALG3):​n.*943T>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,588,802 control chromosomes in the GnomAD database, including 41,130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4372 hom., cov: 32)
  • Exomes 𝑓: 0.22 (36758 hom.)
• Consequence: ALG3 ENST00000411922.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.158
• Publications: 16 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 3-184242464-A-C is Benign according to our data. Variant chr3-184242464-A-C is described in ClinVar as Benign. ClinVar VariationId is 259884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG3	NM_005787.6	c.*50T>G		3_prime_UTR_variant	Exon 9 of 9	ENST00000397676.8	NP_005778.1
VWA5B2	NM_001390846.1	c.*426A>C		downstream_gene_variant		ENST00000691901.1	NP_001377775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG3	ENST00000397676.8	c.*50T>G		3_prime_UTR_variant	Exon 9 of 9	1	NM_005787.6	ENSP00000380793.3
VWA5B2	ENST00000691901.1	c.*426A>C		downstream_gene_variant			NM_001390846.1	ENSP00000509115.1

Frequencies

GnomAD3 genomes AF: 0.237 AC: 35965 AN: 151998 Hom.: 4365 Cov.: 32

Gnomad AFR AF: 0.291

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.164

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.239

GnomAD2 exomes AF: 0.210 AC: 44719 AN: 213090 AF XY: 0.210

Gnomad AFR exome AF: 0.283

Gnomad AMR exome AF: 0.162

Gnomad ASJ exome AF: 0.168

Gnomad EAS exome AF: 0.188

Gnomad FIN exome AF: 0.191

Gnomad NFE exome AF: 0.222

Gnomad OTH exome AF: 0.208

GnomAD4 exome AF: 0.224 AC: 321910 AN: 1436684 Hom.: 36758 Cov.: 31 AF XY: 0.223 AC XY: 159129 AN XY: 712494

African (AFR) AF: 0.292 AC: 9703 AN: 33210

American (AMR) AF: 0.169 AC: 6730 AN: 39786

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 4352 AN: 25646

East Asian (EAS) AF: 0.166 AC: 6496 AN: 39050

South Asian (SAS) AF: 0.224 AC: 18597 AN: 82906

European-Finnish (FIN) AF: 0.190 AC: 9924 AN: 52154

Middle Eastern (MID) AF: 0.232 AC: 1256 AN: 5422

European-Non Finnish (NFE) AF: 0.229 AC: 251688 AN: 1098902

Other (OTH) AF: 0.221 AC: 13164 AN: 59608

GnomAD4 genome AF: 0.237 AC: 35991 AN: 152118 Hom.: 4372 Cov.: 32 AF XY: 0.232 AC XY: 17250 AN XY: 74362

African (AFR) AF: 0.291 AC: 12067 AN: 41464

American (AMR) AF: 0.213 AC: 3258 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 567 AN: 3466

East Asian (EAS) AF: 0.189 AC: 977 AN: 5164

South Asian (SAS) AF: 0.226 AC: 1090 AN: 4824

European-Finnish (FIN) AF: 0.195 AC: 2064 AN: 10610

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.224 AC: 15262 AN: 67984

Other (OTH) AF: 0.237 AC: 500 AN: 2112

Alfa AF: 0.227 Hom.: 1869

Bravo AF: 0.239

Asia WGS AF: 0.235 AC: 822 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ALG3-congenital disorder of glycosylation Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.8
DANN	Benign	0.45
PhyloP100		0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs706584; hg19: chr3-183960252; COSMIC: COSV56611079; COSMIC: COSV56611079;