rs201820102

chrX-111759999-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001099922.3(ALG13):c.3414A>C(p.Ter1138TyrextTer5) variant causes a stop lost change. The variant allele was found at a frequency of 0.00129 in 1,206,161 control chromosomes in the GnomAD database, including 2 homozygotes. There are 483 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 0.00087 (0 hom., 20 hem., cov: 23)
  • Exomes 𝑓: 0.0013 (2 hom. 463 hem.)
• Consequence: ALG13 NM_001099922.3 stop_lost
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.58

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.279615).
• BP6: Variant X-111759999-A-C is Benign according to our data. Variant chrX-111759999-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 377466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-111759999-A-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000866 (97/112012) while in subpopulation NFE AF= 0.00152 (81/53243). AF 95% confidence interval is 0.00125. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 20 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALG13	NM_001099922.3	c.3414A>C	p.Ter1138TyrextTer5	stop_lost	27/27	ENST00000394780.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG13	ENST00000394780.8	c.3414A>C	p.Ter1138TyrextTer5	stop_lost	27/27	2	NM_001099922.3	A2

Frequencies

GnomAD3 genomes AF: 0.000866 AC: 97 AN: 111960 Hom.: 0 Cov.: 23 AF XY: 0.000586 AC XY: 20 AN XY: 34112

Gnomad AFR AF: 0.000357

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000380

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000374

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00152

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000645 AC: 113 AN: 175314 Hom.: 0 AF XY: 0.000598 AC XY: 38 AN XY: 63508

Gnomad AFR exome AF: 0.000245

Gnomad AMR exome AF: 0.000149

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000746

Gnomad SAS exome AF: 0.000166

Gnomad FIN exome AF: 0.0000636

Gnomad NFE exome AF: 0.00126

Gnomad OTH exome AF: 0.000691

GnomAD4 exome AF: 0.00133 AC: 1457 AN: 1094149 Hom.: 2 Cov.: 30 AF XY: 0.00129 AC XY: 463 AN XY: 359889

Gnomad4 AFR exome AF: 0.000114

Gnomad4 AMR exome AF: 0.000115

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000332

Gnomad4 SAS exome AF: 0.000262

Gnomad4 FIN exome AF: 0.000347

Gnomad4 NFE exome AF: 0.00163

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.000866 AC: 97 AN: 112012 Hom.: 0 Cov.: 23 AF XY: 0.000585 AC XY: 20 AN XY: 34174

Gnomad4 AFR AF: 0.000356

Gnomad4 AMR AF: 0.000380

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000375

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00152

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00124 Hom.: 51

Bravo AF: 0.000737

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00138 AC: 4

ESP6500AA AF: 0.000761 AC: 2

ESP6500EA AF: 0.00164 AC: 9

ExAC AF: 0.000715 AC: 86

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Developmental and epileptic encephalopathy, 36 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 21, 2018

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

ALG13-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 06, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	9.8
Dann	Benign	0.82
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	N;N
Vest4		0.18
GERP RS		5.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs201820102; hg19: chrX-111003227;