rs1556449735

Positions:

• chrX-111685093-T-G

Variant summary

Our verdict is Likely benign. Variant got -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

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]

ACMG classification

Verdict is Likely_benign. Variant got -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/exons	MANE	UniProt
ALG13	NM_001099922.3	c.373T>G	p.Cys125Gly	missense_variant	3/27	ENST00000394780.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG13	ENST00000394780.8	c.373T>G	p.Cys125Gly	missense_variant	3/27	2	NM_001099922.3	A2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000290

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000664

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000870

GnomAD4 genome Cov.: 23

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

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	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 (Invitae). ClinVar contains an entry for this variant (Variation ID: 473118). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 03, 2022	- -

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
MutationTaster	Benign	0.96	N;N;N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1556449735; hg19: chrX-110928321;