X-111708970-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001099922.3(ALG13):c.756T>G(p.Phe252Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000127 in 1,176,936 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. F252F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000063 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.0000075 (0 hom. 3 hem.)
• Consequence: ALG13 NM_001099922.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.35

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

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant X-111708970-T-G is Benign according to our data. Variant chrX-111708970-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 574279.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000626 (7/111897) while in subpopulation AMR AF= 0.000568 (6/10565). AF 95% confidence interval is 0.000247. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALG13	NM_001099922.3	c.756T>G	p.Phe252Leu	missense_variant	5/27	ENST00000394780.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG13	ENST00000394780.8	c.756T>G	p.Phe252Leu	missense_variant	5/27	2	NM_001099922.3	A2
ALG13-AS1	ENST00000430794.1	n.106+2026A>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000626 AC: 7 AN: 111897 Hom.: 0 Cov.: 23 AF XY: 0.0000587 AC XY: 2 AN XY: 34055

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000568

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: 0.00

Gnomad OTH AF: 0.000662

GnomAD3 exomes AF: 0.00000685 AC: 1 AN: 145969 Hom.: 0 AF XY: 0.0000230 AC XY: 1 AN XY: 43507

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000421

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000751 AC: 8 AN: 1065039 Hom.: 0 Cov.: 24 AF XY: 0.00000887 AC XY: 3 AN XY: 338383

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000927

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: 0.000112

GnomAD4 genome AF: 0.0000626 AC: 7 AN: 111897 Hom.: 0 Cov.: 23 AF XY: 0.0000587 AC XY: 2 AN XY: 34055

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000568

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000662

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000227

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 01, 2016

The p.F252L variant (also known as c.756T>G), located in coding exon 5 of the ALG13 gene, results from a T to G substitution at nucleotide position 756. The phenylalanine at codon 252 is replaced by leucine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 5147 samples with coverage at this position. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Developmental and epileptic encephalopathy, 36 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 31, 2022

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 252 of the ALG13 protein (p.Phe252Leu). This variant is present in population databases (no rsID available, gnomAD 0.004%), including at least one homozygous and/or hemizygous individual. 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: 574279). 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. 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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 28, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	23
Dann	Uncertain	0.98
DEOGEN2	Benign	0.30	T;.;.;.;.
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.78	T;T;.;T;.
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.47	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.;.;.;.
MutationTaster	Benign	0.98	N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.0	N;.;N;.;.
REVEL	Benign	0.20
Sift	Benign	0.41	T;.;T;.;.
Sift4G	Benign	0.18	T;T;T;T;T
Polyphen		1.0	D;D;D;D;D
Vest4		0.55
MutPred		0.43		Gain of catalytic residue at F252 (P = 0.0344);.;.;.;.;
MVP		0.82
MPC		0.77
ClinPred		0.68	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.56

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs915629293; hg19: chrX-110952198;