dbSNP rs199689080: ALG14:p.Arg109Leu (chr1-95027223-C-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_144988.4(ALG14):c.326G>T(p.Arg109Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R109Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ALG14
NM_144988.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.27

Publications

5 publications found

Variant links:

Genes affected

ALG14 (HGNC:28287): (ALG14 UDP-N-acetylglucosaminyltransferase subunit) This gene is a member of the glycosyltransferase 1 family. The encoded protein and ALG13 are thought to be subunits of UDP-GlcNAc transferase, which catalyzes the first two committed steps in endoplasmic reticulum N-linked glycosylation. Mutations in this gene have been linked to congenital myasthenic syndrome (CMSWTA). Alternatively spliced transcript variants have been identified. [provided by RefSeq, Mar 2015]

ALG14 links:

CNN3-DT (HGNC:54176): (CNN3 divergent transcript)

CNN3-DT links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG14	NM_144988.4 link	c.326G>T	p.Arg109Leu	missense_variant	Exon 3 of 4	ENST00000370205.6	NP_659425.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ALG14	ENST00000370205.6 link	c.326G>T	p.Arg109Leu	missense_variant	Exon 3 of 4	1	NM_144988.4	ENSP00000359224.4
CNN3-DT	ENST00000715651.1 link	n.1005-39821C>A		intron_variant	Intron 2 of 2
ALG14	ENST00000507727.2 link	n.-20G>T		upstream_gene_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

251426

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461828

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111966

Other (OTH)

AF:

0.0000166

AC:

AN:

60394

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.97

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.66

MutationAssessor

Pathogenic

4.3

PhyloP100

5.3

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-6.1

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.90

MutPred

0.98

Loss of disorder (P = 0.0404);

MVP

0.95

MPC

1.3

ClinPred

1.0

GERP RS

5.6

Varity_R

0.94

gMVP

0.89

Mutation Taster

=36/64

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over