rs753556936

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrX-111711720-C-G
• chrX-111711720-C-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3 BP6 BS1 BS2

The NM_001099922.3(ALG13):​c.880C>G​(p.Pro294Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000914 in 1,202,944 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 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. P294S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000082 (0 hom. 6 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 -8 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765
• BP6: Variant X-111711720-C-G is Benign according to our data. Variant chrX-111711720-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 589561.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00000825 (9/1091078) while in subpopulation AMR AF = 0.000259 (9/34762). AF 95% confidence interval is 0.000134. There are 0 homozygotes in GnomAdExome4. There are 6 alleles in the male GnomAdExome4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High Hemizygotes in GnomAdExome4 at 6 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>G	p.Pro294Ala	missense	Exon 6 of 27	NP_001093392.1	Q9NP73-1
	ALG13	NM_001257231.2		c.646C>G	p.Pro216Ala	missense	Exon 6 of 27	NP_001244160.1	Q9NP73-3
	ALG13	NM_001324292.2		c.880C>G	p.Pro294Ala	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>G	p.Pro294Ala	missense	Exon 6 of 27	ENSP00000378260.3	Q9NP73-1
	ALG13	ENST00000927365.1		c.880C>G	p.Pro294Ala	missense	Exon 6 of 27	ENSP00000597424.1
	ALG13	ENST00000927366.1		c.880C>G	p.Pro294Ala	missense	Exon 6 of 25	ENSP00000597425.1

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111866 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000947

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000278

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: 0.0000404 AC: 7 AN: 173246 AF XY: 0.0000488

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000270

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000825 AC: 9 AN: 1091078 Hom.: 0 Cov.: 28 AF XY: 0.0000168 AC XY: 6 AN XY: 357022

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

American (AMR) AF: 0.000259 AC: 9 AN: 34762

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

East Asian (EAS) AF: 0.00 AC: 0 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: 0.0000179 AC: 2 AN: 111866 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34102

African (AFR) AF: 0.00 AC: 0 AN: 30728

American (AMR) AF: 0.0000947 AC: 1 AN: 10561

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

East Asian (EAS) AF: 0.000278 AC: 1 AN: 3594

South Asian (SAS) AF: 0.00 AC: 0 AN: 2710

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53186

Other (OTH) AF: 0.00 AC: 0 AN: 1506

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000333 AC: 4

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.1
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Benign	0.22
Sift	Uncertain	0.010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.23		Loss of glycosylation at P294 (P = 0.0692)
MVP		0.50
MPC		0.70
ClinPred		0.59	D
GERP RS		5.7
Varity_R		0.50
gMVP		0.39
Mutation Taster		=87/13	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;