rs374174400

Variant names:

• chrX-111727736-A-G
• rs374174400
• NM_001099922.3:c.2213A>G
• ALG13 p.Glu738Gly

Variant summary

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

The NM_001099922.3(ALG13):​c.2213A>G​(p.Glu738Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000612 in 1,208,386 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 27 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 4 hem., cov: 23)
  • Exomes 𝑓: 0.000063 (0 hom. 23 hem.)
• Consequence: ALG13 NM_001099922.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 6.28
• Publications: 1 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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-111727736-A-G is Benign according to our data. Variant chrX-111727736-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 238291.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000629 (69/1096386) while in subpopulation NFE AF = 0.0000773 (65/841353). AF 95% confidence interval is 0.0000621. There are 0 homozygotes in GnomAdExome4. There are 23 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 4 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.2213A>G	p.Glu738Gly	missense	Exon 18 of 27	NP_001093392.1	Q9NP73-1
	ALG13	NM_001257231.2		c.1979A>G	p.Glu660Gly	missense	Exon 18 of 27	NP_001244160.1	Q9NP73-3
	ALG13	NM_001324292.2		c.2213A>G	p.Glu738Gly	missense	Exon 18 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.2213A>G	p.Glu738Gly	missense	Exon 18 of 27	ENSP00000378260.3	Q9NP73-1
	ALG13	ENST00000927365.1		c.2189A>G	p.Glu730Gly	missense	Exon 18 of 27	ENSP00000597424.1
	ALG13	ENST00000927366.1		c.2039A>G	p.Glu680Gly	missense	Exon 16 of 25	ENSP00000597425.1

Frequencies

GnomAD3 genomes AF: 0.0000446 AC: 5 AN: 112000 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000324

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: 0.0000752

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000400 AC: 7 AN: 175162 AF XY: 0.0000476

Gnomad AFR exome AF: 0.0000822

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: 0.0000774

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000629 AC: 69 AN: 1096386 Hom.: 0 Cov.: 30 AF XY: 0.0000636 AC XY: 23 AN XY: 361892

African (AFR) AF: 0.0000379 AC: 1 AN: 26375

American (AMR) AF: 0.00 AC: 0 AN: 35069

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19336

East Asian (EAS) AF: 0.00 AC: 0 AN: 30163

South Asian (SAS) AF: 0.00 AC: 0 AN: 53462

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40475

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.0000773 AC: 65 AN: 841353

Other (OTH) AF: 0.0000652 AC: 3 AN: 46020

GnomAD4 genome AF: 0.0000446 AC: 5 AN: 112000 Hom.: 0 Cov.: 23 AF XY: 0.000117 AC XY: 4 AN XY: 34168

African (AFR) AF: 0.0000324 AC: 1 AN: 30833

American (AMR) AF: 0.00 AC: 0 AN: 10547

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3572

South Asian (SAS) AF: 0.00 AC: 0 AN: 2666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000752 AC: 4 AN: 53225

Other (OTH) AF: 0.00 AC: 0 AN: 1495

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000907

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Developmental and epileptic encephalopathy, 36 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		6.3
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.50
Mutation Taster		=98/2	polymorphism

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs374174400;

hg19: chrX-110970964;