rs1336047164

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP2PP3

The NM_005787.6(ALG3):c.194C>T(p.Ala65Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000241 in 1,246,132 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000068 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000018 ( 0 hom. )

Consequence

ALG3
NM_005787.6 missense, splice_region

Scores

Splicing: ADA: 0.9995

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 8.23

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

ALG3-congenital disorder of glycosylation
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen, PanelApp Australia, Orphanet

ALG3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: -0.31675 (below the threshold of 3.09). Trascript score misZ: 0.74965 (below the threshold of 3.09). GenCC associations: The gene is linked to ALG3-congenital disorder of glycosylation.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG3	NM_005787.6 link	c.194C>T	p.Ala65Val	missense_variant, splice_region_variant	Exon 1 of 9	ENST00000397676.8	NP_005778.1	Q92685-1
ALG3	NR_024533.1 link	n.225C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 8
ALG3	NM_001006941.2 link	c.52+479C>T		intron_variant	Intron 1 of 8		NP_001006942.1	Q92685-2
ALG3	NR_024534.1 link	n.190+35C>T		intron_variant	Intron 1 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG3	ENST00000397676.8 link	c.194C>T	p.Ala65Val	missense_variant, splice_region_variant	Exon 1 of 9	1	NM_005787.6	ENSP00000380793.3		Q92685-1

Frequencies

GnomAD3 genomes

AF:

0.00000676

AC:

AN:

147854

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1098278

Hom.:

Cov.:

AF XY:

0.00000184

AC XY:

AN XY:

542808

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24066

American (AMR)

AF:

0.00

AC:

AN:

32280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16356

East Asian (EAS)

AF:

0.00

AC:

AN:

22764

South Asian (SAS)

AF:

0.00

AC:

AN:

77778

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34136

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3932

European-Non Finnish (NFE)

AF:

0.00000236

AC:

AN:

845974

Other (OTH)

AF:

0.00

AC:

AN:

40992

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000676

AC:

AN:

147854

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72058

show subpopulations

African (AFR)

AF:

0.0000246

AC:

AN:

40582

American (AMR)

AF:

0.00

AC:

AN:

14848

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3438

East Asian (EAS)

AF:

0.00

AC:

AN:

4666

South Asian (SAS)

AF:

0.00

AC:

AN:

4406

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9760

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66910

Other (OTH)

AF:

0.00

AC:

AN:

2042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Feb 17, 2017

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 03, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on splicing; In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.55

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.97

M_CAP

Benign

0.076

MetaRNN

Uncertain

0.64

MetaSVM

Uncertain

0.23

MutationAssessor

Uncertain

2.3

PhyloP100

8.2

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.63

Sift

Uncertain

0.012

Sift4G

Uncertain

0.025

Polyphen

0.070

Vest4

0.59

MutPred

0.60

Gain of sheet (P = 0.1208);

MVP

0.94

MPC

0.18

ClinPred

0.97

GERP RS

5.4

PromoterAI

0.075

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.82

gMVP

0.83

Mutation Taster

=55/45

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.63

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.63

Position offset: 2

DS_DL_spliceai

0.60

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs1336047164

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over