Genetic Variant ALG3:p.Leu5Arg (chr3-184248927-A-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_005787.6(ALG3):c.14T>G(p.Leu5Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,431,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L5V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ALG3
NM_005787.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.14

Publications

1 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 1 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.10181606).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG3	NM_005787.6 link	c.14T>G	p.Leu5Arg	missense_variant	Exon 1 of 9	ENST00000397676.8	NP_005778.1	Q92685-1
ALG3	NR_024533.1 link	n.45T>G		non_coding_transcript_exon_variant	Exon 1 of 8
ALG3	NR_024534.1 link	n.45T>G		non_coding_transcript_exon_variant	Exon 1 of 9
ALG3	NM_001006941.2 link	c.52+299T>G		intron_variant	Intron 1 of 8		NP_001006942.1	Q92685-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG3	ENST00000397676.8 link	c.14T>G	p.Leu5Arg	missense_variant	Exon 1 of 9	1	NM_005787.6	ENSP00000380793.3		Q92685-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000506

AC:

AN:

197636

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000116

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000210

AC:

AN:

1431554

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

709350

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32980

American (AMR)

AF:

0.00

AC:

AN:

41270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25656

East Asian (EAS)

AF:

0.00

AC:

AN:

38446

South Asian (SAS)

AF:

0.00

AC:

AN:

83736

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46304

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.00000182

AC:

AN:

1098274

Other (OTH)

AF:

0.0000169

AC:

AN:

59172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.079

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.72

M_CAP

Benign

0.077

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.5

PhyloP100

1.1

PrimateAI

Uncertain

0.58

PROVEAN

Benign

0.74

REVEL

Uncertain

0.31

Sift

Benign

0.88

Sift4G

Benign

0.83

Polyphen

0.013

Vest4

0.43

MVP

0.84

MPC

0.13

ClinPred

0.21

GERP RS

4.5

PromoterAI

0.11

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.0

Varity_R

0.32

gMVP

0.54

Mutation Taster

=85/15

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over