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

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

2
Splicing: ADA: 0.004647
2

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

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
ALG13NM_001099922.3 linkc.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
ALG13ENST00000394780.8 linkc.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.:
14
Cov.:
23
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.:
16
Cov.:
30
AF XY:
0.00435
AC XY:
1580
AN XY:
363120
show subpopulations
African (AFR)
AF:
0.000189
AC:
5
AN:
26387
American (AMR)
AF:
0.000739
AC:
26
AN:
35198
Ashkenazi Jewish (ASJ)
AF:
0.000103
AC:
2
AN:
19372
East Asian (EAS)
AF:
0.00
AC:
0
AN:
30192
South Asian (SAS)
AF:
0.0188
AC:
1018
AN:
54084
European-Finnish (FIN)
AF:
0.00190
AC:
77
AN:
40499
Middle Eastern (MID)
AF:
0.00442
AC:
18
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
0
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
0
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.:
14
Cov.:
23
AF XY:
0.00327
AC XY:
111
AN XY:
33931
show subpopulations
African (AFR)
AF:
0.000520
AC:
16
AN:
30776
American (AMR)
AF:
0.000761
AC:
8
AN:
10516
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
2648
East Asian (EAS)
AF:
0.00
AC:
0
AN:
3542
South Asian (SAS)
AF:
0.0154
AC:
41
AN:
2670
European-Finnish (FIN)
AF:
0.000995
AC:
6
AN:
6028
Middle Eastern (MID)
AF:
0.00917
AC:
2
AN:
218
European-Non Finnish (NFE)
AF:
0.00369
AC:
196
AN:
53152
Other (OTH)
AF:
0.00263
AC:
4
AN:
1519
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.505
Heterozygous variant carriers
0
13
26
38
51
64
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
4
8
12
16
20
<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.:
16
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
DANN
Benign
0.80
PhyloP100
0.057
Mutation Taster
=96/4
polymorphism (auto)

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

Other links and lift over

dbSNP: rs370438099; hg19: chrX-110971409; API