rs374231091

chrX-111726922-C-GchrX-111726922-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001099922.3(ALG13):c.1843C>G(p.Leu615Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,057 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. 12/19 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. L615R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: ALG13 NM_001099922.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.136

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.091132075).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALG13	NM_001099922.3	c.1843C>G	p.Leu615Val	missense_variant	16/27	ENST00000394780.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG13	ENST00000394780.8	c.1843C>G	p.Leu615Val	missense_variant	16/27	2	NM_001099922.3	A2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098057 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363493

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 36 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 01, 2022

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ALG13 protein function. ClinVar contains an entry for this variant (Variation ID: 1379963). This variant has not been reported in the literature in individuals affected with ALG13-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 615 of the ALG13 protein (p.Leu615Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	8.9
Dann	Uncertain	0.99
DEOGEN2	Benign	0.37	T;.;.;.;.;T
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.64	T;T;.;T;.;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.091	T;T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.7	L;.;.;.;.;.
MutationTaster	Benign	0.85	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.4	N;.;N;.;.;.
REVEL	Benign	0.073
Sift	Uncertain	0.0070	D;.;D;.;.;.
Sift4G	Uncertain	0.0060	D;D;D;D;D;D
Polyphen		0.18	B;B;P;P;P;.
Vest4		0.33
MutPred		0.17		Gain of catalytic residue at L615 (P = 0.0476);.;.;.;.;.;
MVP		0.36
MPC		0.18
ClinPred		0.12	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.23

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-110970150;