X-111681260-C-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001099922.3(ALG13):c.42C>A(p.Asp14Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000355 in 1,211,182 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000071 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.000032 (0 hom. 10 hem.)
• Consequence: ALG13 NM_001099922.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.691

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 Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08679962).
• BP6: Variant X-111681260-C-A is Benign according to our data. Variant chrX-111681260-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 517036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000707 (8/113092) while in subpopulation AMR AF= 0.000737 (8/10849). AF 95% confidence interval is 0.000366. There are 0 homozygotes in gnomad4. There are 1 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAdExome at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALG13	NM_001099922.3	c.42C>A	p.Asp14Glu	missense_variant	1/27	ENST00000394780.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG13	ENST00000394780.8	c.42C>A	p.Asp14Glu	missense_variant	1/27	2	NM_001099922.3	A2

Frequencies

GnomAD3 genomes AF: 0.0000708 AC: 8 AN: 113041 Hom.: 0 Cov.: 24 AF XY: 0.0000284 AC XY: 1 AN XY: 35179

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000738

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: 0.00

GnomAD3 exomes AF: 0.000175 AC: 32 AN: 183190 Hom.: 0 AF XY: 0.000118 AC XY: 8 AN XY: 67664

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00113

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: 0.000221

GnomAD4 exome AF: 0.0000319 AC: 35 AN: 1098090 Hom.: 0 Cov.: 30 AF XY: 0.0000275 AC XY: 10 AN XY: 363448

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000881

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: 0.0000868

GnomAD4 genome AF: 0.0000707 AC: 8 AN: 113092 Hom.: 0 Cov.: 24 AF XY: 0.0000284 AC XY: 1 AN XY: 35240

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000737

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: 0.00

Bravo AF: 0.0000793

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 36 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 16, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 24, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	24
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	D;T;D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Benign	0.087	T;T;T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.7	L;L;.;.;.
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.8	D;N;.;.;.
REVEL	Uncertain	0.45
Sift	Benign	0.11	T;T;.;.;.
Sift4G	Benign	0.11	T;T;T;T;T
Polyphen		0.18	B;D;.;.;.
Vest4		0.38
MutPred		0.57		Loss of stability (P = 0.1242);Loss of stability (P = 0.1242);Loss of stability (P = 0.1242);Loss of stability (P = 0.1242);.;
MVP		0.85
MPC		0.67
ClinPred		0.20	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs200293248; hg19: chrX-110924488;