chrX-111708031-C-G

Variant names:

• chrX-111708031-C-G
• rs1381653955
• NM_001099922.3:c.388C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001099922.3(ALG13):​c.388C>G​(p.Leu130Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000896 in 111,602 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L130P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: ALG13 NM_001099922.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.233

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-AS1 (HGNC:41277): (ALG13 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1201067).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG13	NM_001099922.3	c.388C>G	p.Leu130Val	missense_variant	Exon 4 of 27	ENST00000394780.8	NP_001093392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG13	ENST00000394780.8	c.388C>G	p.Leu130Val	missense_variant	Exon 4 of 27	2	NM_001099922.3	ENSP00000378260.3

Frequencies

GnomAD3 genomes AF: 0.00000896 AC: 1 AN: 111602 Hom.: 0 Cov.: 22

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000183 AC: 2 AN: 1092986 Hom.: 0 Cov.: 31 AF XY: 0.00000279 AC XY: 1 AN XY: 358950

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 26330

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 34859

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 19138

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 30136

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 53087

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 40063

Gnomad4 NFE exome AF: 0.00000238 AC: 2 AN: 839439

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 45892

GnomAD4 genome AF: 0.00000896 AC: 1 AN: 111602 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33778

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000188 AC: 0.000018809 AN: 0.000018809

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 36 Uncertain:1

Jun 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 130 of the ALG13 protein (p.Leu130Val). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ALG13-related conditions. ClinVar contains an entry for this variant (Variation ID: 862507). 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 tolerated. 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	0.076
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	3.2
DANN	Benign	0.79
DEOGEN2	Benign	0.20	T;.;.;.;.
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.64	T;T;.;T;.
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.12	T;T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Pathogenic	3.4	M;.;.;.;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.70	N;.;N;.;.
REVEL	Benign	0.10
Sift	Uncertain	0.010	D;.;D;.;.
Sift4G	Uncertain	0.037	D;D;T;T;T
Polyphen		0.080	B;B;B;B;B
Vest4		0.13
MVP		0.79
MPC		0.27
ClinPred		0.20	T
GERP RS		-0.45
Varity_R		0.099
gMVP		0.14
Mutation Taster		=100/0	polymorphism

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1381653955; hg19: chrX-110951259; COSMIC: COSV99322989;