chrX-111730398-G-A

Variant names:

• chrX-111730398-G-A
• rs374290658
• NM_001099922.3:c.2372G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001099922.3(ALG13):​c.2372G>A​(p.Arg791Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000639 in 1,095,565 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R791R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000064 (0 hom. 4 hem.)
• Consequence: ALG13 NM_001099922.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 0.589
• 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: 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08882591).
• BS2: High Hemizygotes in GnomAdExome4 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.2372G>A	p.Arg791Gln	missense	Exon 20 of 27	NP_001093392.1	Q9NP73-1
	ALG13	NM_001257231.2		c.2138G>A	p.Arg713Gln	missense	Exon 20 of 27	NP_001244160.1	Q9NP73-3
	ALG13	NM_001324292.2		c.2372G>A	p.Arg791Gln	missense	Exon 20 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.2372G>A	p.Arg791Gln	missense	Exon 20 of 27	ENSP00000378260.3	Q9NP73-1
	ALG13	ENST00000927365.1		c.2348G>A	p.Arg783Gln	missense	Exon 20 of 27	ENSP00000597424.1
	ALG13	ENST00000927366.1		c.2198G>A	p.Arg733Gln	missense	Exon 18 of 25	ENSP00000597425.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00000565 AC: 1 AN: 177099 AF XY: 0.00

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: 0.0000128

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000639 AC: 7 AN: 1095565 Hom.: 0 Cov.: 29 AF XY: 0.0000111 AC XY: 4 AN XY: 361251

African (AFR) AF: 0.00 AC: 0 AN: 26358

American (AMR) AF: 0.00 AC: 0 AN: 35106

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19354

East Asian (EAS) AF: 0.00 AC: 0 AN: 30170

South Asian (SAS) AF: 0.00 AC: 0 AN: 53868

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40459

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4064

European-Non Finnish (NFE) AF: 0.00000833 AC: 7 AN: 840198

Other (OTH) AF: 0.00 AC: 0 AN: 45988

GnomAD4 genome Cov.: 24

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000182 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy, 36 (1)
-	1	-	not provided (1)
-	-	-	Congenital disorder of glycosylation;C4317295:Developmental and epileptic encephalopathy, 36 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.0
DANN	Benign	0.67
DEOGEN2	Benign	0.14	T
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.59
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.018
Sift	Benign	0.43	T
Sift4G	Benign	0.33	T
Polyphen		0.063	B
Vest4		0.077
MVP		0.28
MPC		0.21
ClinPred		0.014	T
GERP RS		-3.2
Varity_R		0.033
gMVP		0.24
Mutation Taster		=97/3	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs374290658; hg19: chrX-110973626; COSMIC: COSV99322575; COSMIC: COSV99322575;