rs2233466

chr3-184243878-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_005787.6(ALG3):c.845C>T(p.Ala282Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000312 in 1,614,008 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A282A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: ALG3 NM_005787.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 2.56

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0148973465).
• BP6: Variant 3-184243878-G-A is Benign according to our data. Variant chr3-184243878-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 344352.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000919 (140/152352) while in subpopulation AFR AF= 0.00279 (116/41582). AF 95% confidence interval is 0.00238. There are 0 homozygotes in gnomad4. There are 63 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALG3	NM_005787.6	c.845C>T	p.Ala282Val	missense_variant	6/9	ENST00000397676.8
ALG3	NM_001006941.2	c.701C>T	p.Ala234Val	missense_variant	6/9
ALG3	NR_024533.1	n.776C>T		non_coding_transcript_exon_variant	5/8
ALG3	NR_024534.1	n.839C>T		non_coding_transcript_exon_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG3	ENST00000397676.8	c.845C>T	p.Ala282Val	missense_variant	6/9	1	NM_005787.6	P1

Frequencies

GnomAD3 genomes AF: 0.000920 AC: 140 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00280

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000503 AC: 125 AN: 248602 Hom.: 0 AF XY: 0.000407 AC XY: 55 AN XY: 135044

Gnomad AFR exome AF: 0.00260

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00488

Gnomad EAS exome AF: 0.00128

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000356

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000248 AC: 363 AN: 1461656 Hom.: 1 Cov.: 31 AF XY: 0.000228 AC XY: 166 AN XY: 727114

Gnomad4 AFR exome AF: 0.00281

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00528

Gnomad4 EAS exome AF: 0.00154

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.000580

GnomAD4 genome AF: 0.000919 AC: 140 AN: 152352 Hom.: 0 Cov.: 32 AF XY: 0.000846 AC XY: 63 AN XY: 74506

Gnomad4 AFR AF: 0.00279

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000449 Hom.: 0

Bravo AF: 0.00109

ESP6500AA AF: 0.00221 AC: 9

ESP6500EA AF: 0.000358 AC: 3

ExAC AF: 0.000471 AC: 57

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

ALG3-congenital disorder of glycosylation Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Sep 10, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Jul 19, 2017

- -

ALG3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.31	T;.;.
Eigen	Benign	0.031
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.015	T;T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.2	L;.;.
MutationTaster	Benign	1.0	N;N;N;N;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.26
Sift	Benign	0.29	T;T;T
Sift4G	Benign	0.062	T;D;D
Polyphen		0.16	B;.;B
Vest4		0.17
MVP		0.95
MPC		0.10
ClinPred		0.0089	T
GERP RS		4.7
Varity_R		0.072
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs2233466; hg19: chr3-183961666; COSMIC: COSV56610767; COSMIC: COSV56610767;