rs1556449735

Variant names:

• chrX-111685093-T-G
• rs1556449735
• NM_001099922.3:c.373T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_001099922.3(ALG13):​c.373T>G​(p.Cys125Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000639 in 1,095,471 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000064 (0 hom. 2 hem.)
• Consequence: ALG13 NM_001099922.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.58
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG13	NM_001099922.3	c.373T>G	p.Cys125Gly	missense_variant	Exon 3 of 27	ENST00000394780.8	NP_001093392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG13	ENST00000394780.8	c.373T>G	p.Cys125Gly	missense_variant	Exon 3 of 27	2	NM_001099922.3	ENSP00000378260.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000639 AC: 7 AN: 1095471 Hom.: 0 Cov.: 29 AF XY: 0.00000554 AC XY: 2 AN XY: 361039

African (AFR) AF: 0.00 AC: 0 AN: 26265

American (AMR) AF: 0.0000290 AC: 1 AN: 34499

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19277

East Asian (EAS) AF: 0.0000664 AC: 2 AN: 30142

South Asian (SAS) AF: 0.00 AC: 0 AN: 53502

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4126

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841170

Other (OTH) AF: 0.0000870 AC: 4 AN: 45992

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 36 Uncertain:2

Apr 03, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 125 of the ALG13 protein (p.Cys125Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (internal data). ClinVar contains an entry for this variant (Variation ID: 473118). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ALG13 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	.;T;.;.;.;T;.;T;.;.;.
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;D;D;.;D;D;D;D;.;.;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.42	T
PhyloP100		5.6
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-10	D;D;.;D;.;.;.;.;.;.;.
REVEL	Uncertain	0.52
Sift	Uncertain	0.0060	D;D;.;D;.;.;.;.;.;.;.
Sift4G	Uncertain	0.013	D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.91	P;B;B;B;B;.;.;.;B;.;.
Vest4		0.88
MutPred		0.71		Loss of stability (P = 0.028);Loss of stability (P = 0.028);.;.;.;Loss of stability (P = 0.028);Loss of stability (P = 0.028);.;.;.;.;
MVP		0.97
MPC		0.79
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.76
gMVP		0.47
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1556449735; hg19: chrX-110928321;