X-111730526-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000394780.8(ALG13):c.2403G>C(p.Glu801Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000386 in 1,192,624 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. 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. E801G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000037 ( 0 hom. 13 hem. )

Consequence

ALG13
ENST00000394780.8 missense, splice_region

Scores

Splicing: ADA: 0.00006577

Clinical Significance

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

Conservation

PhyloP100: 0.256

Publications

3 publications found

Variant links:

Genes affected

ALG13 (HGNC:30881): (ALG13 UDP-N-acetylglucosaminyltransferase subunit) The protein encoded by this gene is a subunit of a bipartite UDP-N-acetylglucosamine transferase. It heterodimerizes with asparagine-linked glycosylation 14 homolog to form a functional UDP-GlcNAc glycosyltransferase that catalyzes the second sugar addition of the highly conserved oligosaccharide precursor in endoplasmic reticulum N-linked glycosylation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2009]

ALG13 Gene-Disease associations (from GenCC):

genetic developmental and epileptic encephalopathy
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy, 36
Inheritance: XL Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
non-syndromic X-linked intellectual disability
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ALG13 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.052847683).

BP6

Variant X-111730526-G-C is Benign according to our data. Variant chrX-111730526-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 403876.

BS2

High Hemizygotes in GnomAdExome4 at 13 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000394780.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ALG13	NM_001099922.3	MANE Select	c.2403G>C	p.Glu801Asp	missense splice_region	Exon 21 of 27	NP_001093392.1
ALG13	NM_001257231.2		c.2169G>C	p.Glu723Asp	missense splice_region	Exon 21 of 27	NP_001244160.1
ALG13	NM_001324292.2		c.2403G>C	p.Glu801Asp	missense splice_region	Exon 21 of 26	NP_001311221.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ALG13	ENST00000394780.8	TSL:2 MANE Select	c.2403G>C	p.Glu801Asp	missense splice_region	Exon 21 of 27	ENSP00000378260.3
ALG13	ENST00000623622.2	TSL:5	c.2229G>C	p.Glu743Asp	missense splice_region	Exon 19 of 24	ENSP00000485624.2
ALG13	ENST00000436609.5	TSL:5	c.2091G>C	p.Glu697Asp	missense splice_region	Exon 21 of 26	ENSP00000392990.2

Frequencies

GnomAD3 genomes

AF:

0.0000537

AC:

AN:

111722

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000113

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000604

AC:

AN:

149099

AF XY:

0.0000219

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:

0.000145

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000370

AC:

AN:

1080902

Hom.:

Cov.:

AF XY:

0.0000370

AC XY:

AN XY:

351148

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26145

American (AMR)

AF:

0.00

AC:

AN:

32940

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19040

East Asian (EAS)

AF:

0.00

AC:

AN:

29793

South Asian (SAS)

AF:

0.00

AC:

AN:

51808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39662

Middle Eastern (MID)

AF:

0.000267

AC:

AN:

3746

European-Non Finnish (NFE)

AF:

0.0000445

AC:

AN:

832331

Other (OTH)

AF:

0.0000440

AC:

AN:

45437

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.0000537

AC:

AN:

111722

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33916

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30747

American (AMR)

AF:

0.00

AC:

AN:

10474

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2640

East Asian (EAS)

AF:

0.00

AC:

AN:

3558

South Asian (SAS)

AF:

0.00

AC:

AN:

2672

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6017

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.000113

AC:

AN:

53180

Other (OTH)

AF:

0.00

AC:

AN:

1511

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

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:

0.00

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.000126

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy, 36 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.79

CADD

Benign

7.6

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.22

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.73

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.053

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PhyloP100

0.26

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.75

REVEL

Benign

0.067

Sift

Benign

0.30

Sift4G

Benign

0.44

Polyphen

0.0020

Vest4

0.12

MutPred

0.12

Loss of phosphorylation at Y798 (P = 0.0837)

MVP

0.34

MPC

0.28

ClinPred

0.053

GERP RS

-2.2

Varity_R

0.087

gMVP

0.30

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000066

dbscSNV1_RF

Benign

0.048

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over