rs201055779

chrX-111757622-A-G

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.3008A>G(p.Tyr1003Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000813 in 1,204,885 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 31 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., 7 hem., cov: 22)
  • Exomes 𝑓: 0.000068 (0 hom. 24 hem.)
• Consequence: ALG13 NM_001099922.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.785

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 (MetaRNN=0.01303643).
• BP6: Variant X-111757622-A-G is Benign according to our data. Variant chrX-111757622-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 390901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000211 (23/109178) while in subpopulation EAS AF= 0.00145 (5/3454). AF 95% confidence interval is 0.00057. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALG13	NM_001099922.3	c.3008A>G	p.Tyr1003Cys	missense_variant	26/27	ENST00000394780.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALG13	ENST00000394780.8	c.3008A>G	p.Tyr1003Cys	missense_variant	26/27	2	NM_001099922.3	A2

Frequencies

GnomAD3 genomes AF: 0.000211 AC: 23 AN: 109131 Hom.: 0 Cov.: 22 AF XY: 0.000222 AC XY: 7 AN XY: 31553

Gnomad AFR AF: 0.000502

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000100

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00144

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000380

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000154 AC: 27 AN: 175055 Hom.: 0 AF XY: 0.000127 AC XY: 8 AN XY: 63157

Gnomad AFR exome AF: 0.000413

Gnomad AMR exome AF: 0.0000374

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00129

Gnomad SAS exome AF: 0.0000549

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000259

Gnomad OTH exome AF: 0.000231

GnomAD4 exome AF: 0.0000684 AC: 75 AN: 1095707 Hom.: 0 Cov.: 30 AF XY: 0.0000664 AC XY: 24 AN XY: 361369

Gnomad4 AFR exome AF: 0.000190

Gnomad4 AMR exome AF: 0.0000571

Gnomad4 ASJ exome AF: 0.0000518

Gnomad4 EAS exome AF: 0.000465

Gnomad4 SAS exome AF: 0.0000372

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000202

Gnomad4 OTH exome AF: 0.000739

GnomAD4 genome AF: 0.000211 AC: 23 AN: 109178 Hom.: 0 Cov.: 22 AF XY: 0.000221 AC XY: 7 AN XY: 31610

Gnomad4 AFR AF: 0.000501

Gnomad4 AMR AF: 0.0000999

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00145

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000380

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000343 Hom.: 0

Bravo AF: 0.000249

ESP6500AA AF: 0.000761 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000166 AC: 20

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 29, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2019	In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 06, 2018

This alteration is classified as likely 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

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 13, 2019

This variant is classified as likely 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
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	7.2
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D;.;.;.;.
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.69	T;T;.;T;.
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.013	T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.7	L;.;.;.;.
MutationTaster	Benign	0.74	N;N
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.0	D;.;D;.;.
REVEL	Benign	0.087
Sift	Uncertain	0.0020	D;.;D;.;.
Sift4G	Uncertain	0.030	D;D;D;D;D
Polyphen		0.0030	B;D;D;D;D
Vest4		0.26
MVP		0.26
MPC		0.22
ClinPred		0.057	T
GERP RS		-0.25
Varity_R		0.39
gMVP		0.22

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs201055779; hg19: chrX-111000850;