NM_001099922.3:c.2248-4A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_001099922.3(ALG13):c.2248-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00366 in 1,209,347 control chromosomes in the GnomAD database, including 30 homozygotes. There are 1,691 hemizygotes in GnomAD. In-silico tool predicts 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 Benign (★★).

Frequency

Genomes: 𝑓 0.0036 ( 14 hom., 111 hem., cov: 23)

Exomes 𝑓: 0.0037 ( 16 hom. 1580 hem. )

Consequence

ALG13
NM_001099922.3 splice_region, intron

Scores

Splicing: ADA: 0.004647

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.0570

Publications

0 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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4).

BP6

Variant X-111728181-A-G is Benign according to our data. Variant chrX-111728181-A-G is described in ClinVar as Benign. ClinVar VariationId is 380781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00362 (404/111747) while in subpopulation SAS AF = 0.0154 (41/2670). AF 95% confidence interval is 0.0116. There are 14 homozygotes in GnomAd4. There are 111 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG13	NM_001099922.3 link	c.2248-4A>G		splice_region_variant, intron_variant	Intron 18 of 26	ENST00000394780.8	NP_001093392.1	Q9NP73-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG13	ENST00000394780.8 link	c.2248-4A>G		splice_region_variant, intron_variant	Intron 18 of 26	2	NM_001099922.3	ENSP00000378260.3		Q9NP73-1

Frequencies

GnomAD3 genomes

AF:

0.00362

AC:

404

AN:

111692

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000521

Gnomad AMI

AF:

0.193

Gnomad AMR

AF:

0.000762

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0153

Gnomad FIN

AF:

0.000995

Gnomad MID

AF:

0.00837

Gnomad NFE

AF:

0.00369

Gnomad OTH

AF:

0.00267

GnomAD2 exomes

AF:

0.00397

AC:

710

AN:

178742

AF XY:

0.00496

show subpopulations

Gnomad AFR exome

AF:

0.000324

Gnomad AMR exome

AF:

0.000658

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00113

Gnomad NFE exome

AF:

0.00360

Gnomad OTH exome

AF:

0.00338

GnomAD4 exome

AF:

0.00366

AC:

4019

AN:

1097600

Hom.:

Cov.:

AF XY:

0.00435

AC XY:

1580

AN XY:

363120

show subpopulations

African (AFR)

AF:

0.000189

AC:

AN:

26387

American (AMR)

AF:

0.000739

AC:

AN:

35198

Ashkenazi Jewish (ASJ)

AF:

0.000103

AC:

AN:

19372

East Asian (EAS)

AF:

0.00

AC:

AN:

30192

South Asian (SAS)

AF:

0.0188

AC:

1018

AN:

54084

European-Finnish (FIN)

AF:

0.00190

AC:

AN:

40499

Middle Eastern (MID)

AF:

0.00442

AC:

AN:

4070

European-Non Finnish (NFE)

AF:

0.00324

AC:

2730

AN:

841743

Other (OTH)

AF:

0.00310

AC:

143

AN:

46055

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

124

247

371

494

618

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

208

312

416

520

<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:

0.00362

AC:

404

AN:

111747

Hom.:

Cov.:

AF XY:

0.00327

AC XY:

111

AN XY:

33931

show subpopulations

African (AFR)

AF:

0.000520

AC:

AN:

30776

American (AMR)

AF:

0.000761

AC:

AN:

10516

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3542

South Asian (SAS)

AF:

0.0154

AC:

AN:

2670

European-Finnish (FIN)

AF:

0.000995

AC:

AN:

6028

Middle Eastern (MID)

AF:

0.00917

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00369

AC:

196

AN:

53152

Other (OTH)

AF:

0.00263

AC:

AN:

1519

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00273

Hom.:

Bravo

AF:

0.00348

EpiCase

AF:

0.00474

EpiControl

AF:

0.00518

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 36

Benign:4

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 04, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Feb 15, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Inborn genetic diseases

Benign:1

Sep 25, 2017

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

2.7

(source)

DANN

Benign

0.80

PhyloP100

0.057

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0046

dbscSNV1_RF

Benign

0.16

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over