3-184242883-C-T

Position:

chr3-184242883-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_005787.6(ALG3):c.1084G>A(p.Val362Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,613,810 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 3 hom. )

Consequence

ALG3
NM_005787.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 7.73

Variant links:

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]

ALG3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020545602).

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000795 (121/152284) while in subpopulation EAS AF= 0.00559 (29/5190). AF 95% confidence interval is 0.004. There are 0 homozygotes in gnomad4. There are 53 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

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ALG3	NM_005787.6 linkuse as main transcript	c.1084G>A	p.Val362Ile	missense_variant	8/9	ENST00000397676.8
ALG3	NM_001006941.2 linkuse as main transcript	c.940G>A	p.Val314Ile	missense_variant	8/9
ALG3	NR_024533.1 linkuse as main transcript	n.1015G>A		non_coding_transcript_exon_variant	7/8
ALG3	NR_024534.1 linkuse as main transcript	n.1078G>A		non_coding_transcript_exon_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG3	ENST00000397676.8 linkuse as main transcript	c.1084G>A	p.Val362Ile	missense_variant	8/9	1	NM_005787.6	P1	Q92685-1

Frequencies

GnomAD3 genomes

AF:

0.000795

AC:

121

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00557

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000472

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00103

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.00121

AC:

300

AN:

248924

Hom.:

AF XY:

0.00115

AC XY:

155

AN XY:

135082

show subpopulations

Gnomad AFR exome

AF:

0.000258

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00139

Gnomad EAS exome

AF:

0.00512

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.000328

Gnomad NFE exome

AF:

0.00140

Gnomad OTH exome

AF:

0.00182

GnomAD4 exome

AF:

0.00147

AC:

2142

AN:

1461526

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

1050

AN XY:

727038

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.000727

Gnomad4 EAS exome

AF:

0.00547

Gnomad4 SAS exome

AF:

0.000290

Gnomad4 FIN exome

AF:

0.000507

Gnomad4 NFE exome

AF:

0.00154

Gnomad4 OTH exome

AF:

0.00199

GnomAD4 genome

AF:

0.000795

AC:

121

AN:

152284

Hom.:

Cov.:

AF XY:

0.000712

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00559

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.000472

Gnomad4 NFE

AF:

0.00103

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.00145

Hom.:

Bravo

AF:

0.000827

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00146

AC:

ESP6500EA

AF:

0.000595

AC:

ExAC

AF:

0.00121

AC:

147

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.00153

EpiControl

AF:

0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published in a patient, as pathogenic or benign, to our knowledge; This variant is associated with the following publications: (PMID: 30061496) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 08, 2017	- -

ALG3-congenital disorder of glycosylation

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	- -
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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 18, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

T;.;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Benign

0.040

MetaRNN

Benign

0.021

T;T;T

MetaSVM

Uncertain

0.23

MutationAssessor

Benign

1.9

L;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.31

N;N;N

REVEL

Uncertain

0.51

Sift

Benign

0.34

T;T;T

Sift4G

Benign

0.41

T;T;T

Polyphen

0.99

D;.;P

Vest4

0.64

MVP

0.84

MPC

0.36

ClinPred

0.020

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.14

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over