Genetic Variant NM_005787.6:c.1084G>A (chr3-184242883-C-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 3P and 12B. PM1PP2BP4_StrongBS1BS2

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V362G) has been classified as Uncertain significance.

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

Publications

8 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics

ALG3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_005787.6

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.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005787.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALG3	NM_005787.6	MANE Select	c.1084G>A	p.Val362Ile	missense	Exon 8 of 9	NP_005778.1	Q92685-1
ALG3	NM_001006941.2		c.940G>A	p.Val314Ile	missense	Exon 8 of 9	NP_001006942.1	Q92685-2
ALG3	NR_024533.1		n.1015G>A		non_coding_transcript_exon	Exon 7 of 8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALG3	ENST00000397676.8	TSL:1 MANE Select	c.1084G>A	p.Val362Ile	missense	Exon 8 of 9	ENSP00000380793.3	Q92685-1
ALG3	ENST00000445626.6	TSL:1	c.940G>A	p.Val314Ile	missense	Exon 8 of 9	ENSP00000402744.2	Q92685-2
ALG3	ENST00000411922.5	TSL:1	n.*660G>A		non_coding_transcript_exon	Exon 7 of 8	ENSP00000394917.1	F8WE30

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

GnomAD2 exomes

AF:

0.00121

AC:

300

AN:

248924

AF XY:

0.00115

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 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

African (AFR)

AF:

0.000179

AC:

AN:

33478

American (AMR)

AF:

0.000268

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.000727

AC:

AN:

26136

East Asian (EAS)

AF:

0.00547

AC:

217

AN:

39700

South Asian (SAS)

AF:

0.000290

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000507

AC:

AN:

53274

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00154

AC:

1716

AN:

1111820

Other (OTH)

AF:

0.00199

AC:

120

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

133

266

400

533

666

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

222

296

370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000795

AC:

121

AN:

152284

Hom.:

Cov.:

AF XY:

0.000712

AC XY:

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41562

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00559

AC:

AN:

5190

South Asian (SAS)

AF:

0.00145

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000472

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00103

AC:

AN:

68026

Other (OTH)

AF:

0.000949

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00124

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

ALG3-congenital disorder of glycosylation (3)

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.040

MetaRNN

Benign

0.021

MetaSVM

Uncertain

0.23

MutationAssessor

Benign

1.9

PhyloP100

7.7

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.31

REVEL

Uncertain

0.51

Sift

Benign

0.34

Sift4G

Benign

0.41

Polyphen

0.99

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

Mutation Taster

=27/73

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over