rs759347694

Variant names:

• chrX-111757759-A-G
• rs759347694
• NM_001099922.3:c.3145A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The NM_001099922.3(ALG13):​c.3145A>G​(p.Asn1049Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,203,325 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1049S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.000012 (0 hom. 10 hem.)
• Consequence: ALG13 NM_001099922.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.661
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12571305).
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000119 (13/1091894) while in subpopulation SAS AF = 0.000228 (12/52735). AF 95% confidence interval is 0.000131. There are 0 homozygotes in GnomAdExome4. There are 10 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Hemizygotes in GnomAdExome4 at 10 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.3145A>G	p.Asn1049Asp	missense	Exon 26 of 27	NP_001093392.1	Q9NP73-1
	ALG13	NM_001257231.2		c.2911A>G	p.Asn971Asp	missense	Exon 26 of 27	NP_001244160.1	Q9NP73-3
	ALG13	NM_001324292.2		c.2908A>G	p.Asn970Asp	missense	Exon 25 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.3145A>G	p.Asn1049Asp	missense	Exon 26 of 27	ENSP00000378260.3	Q9NP73-1
	ALG13	ENST00000927365.1		c.3121A>G	p.Asn1041Asp	missense	Exon 26 of 27	ENSP00000597424.1
	ALG13	ENST00000927366.1		c.2971A>G	p.Asn991Asp	missense	Exon 24 of 25	ENSP00000597425.1

Frequencies

GnomAD3 genomes AF: 0.00000897 AC: 1 AN: 111431 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD2 exomes AF: 0.0000236 AC: 4 AN: 169475 AF XY: 0.0000343

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000119 AC: 13 AN: 1091894 Hom.: 0 Cov.: 30 AF XY: 0.0000279 AC XY: 10 AN XY: 357988

African (AFR) AF: 0.00 AC: 0 AN: 26165

American (AMR) AF: 0.00 AC: 0 AN: 34239

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19057

East Asian (EAS) AF: 0.00 AC: 0 AN: 30098

South Asian (SAS) AF: 0.000228 AC: 12 AN: 52735

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40435

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4053

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 839269

Other (OTH) AF: 0.0000218 AC: 1 AN: 45843

GnomAD4 genome AF: 0.00000897 AC: 1 AN: 111431 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33613

African (AFR) AF: 0.0000326 AC: 1 AN: 30653

American (AMR) AF: 0.00 AC: 0 AN: 10409

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3542

South Asian (SAS) AF: 0.00 AC: 0 AN: 2658

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5982

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53126

Other (OTH) AF: 0.00 AC: 0 AN: 1496

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000166 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.66
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.039
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.019	D
Polyphen		0.46	P
Vest4		0.095
MutPred		0.30		Loss of sheet (P = 0.0357)
MVP		0.64
MPC		0.35
ClinPred		0.35	T
GERP RS		-0.42
Varity_R		0.47
gMVP		0.20
Mutation Taster		=99/1	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs759347694; hg19: chrX-111000987;