X-111711720-C-T

Variant names:

• chrX-111711720-C-T
• rs753556936
• NM_001099922.3:c.880C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001099922.3(ALG13):​c.880C>T​(p.Pro294Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000723 in 1,202,997 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 32 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P294A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000077 (0 hom. 30 hem.)
• Consequence: ALG13 NM_001099922.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.07
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 36

  Inheritance: XL Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant X-111711720-C-T is Benign according to our data. Variant chrX-111711720-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 587533.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000268 (3/111919) while in subpopulation EAS AF = 0.000837 (3/3584). AF 95% confidence interval is 0.000228. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 2 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099922.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG13	NM_001099922.3	MANE Select	c.880C>T	p.Pro294Ser	missense	Exon 6 of 27	NP_001093392.1	Q9NP73-1
	ALG13	NM_001257231.2		c.646C>T	p.Pro216Ser	missense	Exon 6 of 27	NP_001244160.1	Q9NP73-3
	ALG13	NM_001324292.2		c.880C>T	p.Pro294Ser	missense	Exon 6 of 26	NP_001311221.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG13	ENST00000394780.8	TSL:2 MANE Select	c.880C>T	p.Pro294Ser	missense	Exon 6 of 27	ENSP00000378260.3	Q9NP73-1
	ALG13	ENST00000927365.1		c.880C>T	p.Pro294Ser	missense	Exon 6 of 27	ENSP00000597424.1
	ALG13	ENST00000927366.1		c.880C>T	p.Pro294Ser	missense	Exon 6 of 25	ENSP00000597425.1

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 111866 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000835

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

GnomAD2 exomes AF: 0.0000635 AC: 11 AN: 173246 AF XY: 0.0000976

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000841

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000770 AC: 84 AN: 1091078 Hom.: 0 Cov.: 28 AF XY: 0.0000840 AC XY: 30 AN XY: 357022

African (AFR) AF: 0.00 AC: 0 AN: 26225

American (AMR) AF: 0.00 AC: 0 AN: 34762

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19268

East Asian (EAS) AF: 0.00280 AC: 84 AN: 29995

South Asian (SAS) AF: 0.00 AC: 0 AN: 53044

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40397

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3978

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 837611

Other (OTH) AF: 0.00 AC: 0 AN: 45798

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 111919 Hom.: 0 Cov.: 23 AF XY: 0.0000585 AC XY: 2 AN XY: 34165

African (AFR) AF: 0.00 AC: 0 AN: 30795

American (AMR) AF: 0.00 AC: 0 AN: 10574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.000837 AC: 3 AN: 3584

South Asian (SAS) AF: 0.00 AC: 0 AN: 2701

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6005

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53179

Other (OTH) AF: 0.00 AC: 0 AN: 1526

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.000108 AC: 13

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy, 1 (1)
-	-	1	Developmental and epileptic encephalopathy, 36 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.53
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		6.1
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Benign	0.24
Sift	Uncertain	0.018	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.25		Gain of phosphorylation at P294 (P = 0.053)
MVP		0.49
MPC		0.72
ClinPred		0.53	D
GERP RS		5.7
Varity_R		0.56
gMVP		0.49
Mutation Taster		=76/24	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs753556936; hg19: chrX-110954948; COSMIC: COSV52635205; COSMIC: COSV52635205;