rs372521943

Variant names:

• chrX-111717904-A-G
• rs372521943
• NM_001099922.3:c.1064A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_001099922.3(ALG13):​c.1064A>G​(p.Gln355Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000249 in 1,203,755 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000027 (0 hom. 9 hem.)
• Consequence: ALG13 NM_001099922.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.10
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet
• 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=0.2679379).
• BP6: Variant X-111717904-A-G is Benign according to our data. Variant chrX-111717904-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 286496.
• BS2: High Hemizygotes in GnomAdExome4 at 9 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.1064A>G	p.Gln355Arg	missense	Exon 9 of 27	NP_001093392.1	Q9NP73-1
	ALG13	NM_001257231.2		c.830A>G	p.Gln277Arg	missense	Exon 9 of 27	NP_001244160.1	Q9NP73-3
	ALG13	NM_001324292.2		c.1064A>G	p.Gln355Arg	missense	Exon 9 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.1064A>G	p.Gln355Arg	missense	Exon 9 of 27	ENSP00000378260.3	Q9NP73-1
	ALG13	ENST00000927365.1		c.1064A>G	p.Gln355Arg	missense	Exon 9 of 27	ENSP00000597424.1
	ALG13	ENST00000927366.1		c.1064A>G	p.Gln355Arg	missense	Exon 9 of 25	ENSP00000597425.1

Frequencies

GnomAD3 genomes AF: 0.00000898 AC: 1 AN: 111382 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000115 AC: 2 AN: 173453 AF XY: 0.0000163

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: 0.0000260

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000265 AC: 29 AN: 1092373 Hom.: 0 Cov.: 28 AF XY: 0.0000251 AC XY: 9 AN XY: 358073

African (AFR) AF: 0.00 AC: 0 AN: 26277

American (AMR) AF: 0.00 AC: 0 AN: 34909

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19290

East Asian (EAS) AF: 0.00 AC: 0 AN: 30159

South Asian (SAS) AF: 0.00 AC: 0 AN: 53286

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40395

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4115

European-Non Finnish (NFE) AF: 0.0000334 AC: 28 AN: 838040

Other (OTH) AF: 0.0000218 AC: 1 AN: 45902

GnomAD4 genome AF: 0.00000898 AC: 1 AN: 111382 Hom.: 0 Cov.: 22 AF XY: 0.0000298 AC XY: 1 AN XY: 33554

African (AFR) AF: 0.00 AC: 0 AN: 30682

American (AMR) AF: 0.00 AC: 0 AN: 10398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3562

South Asian (SAS) AF: 0.00 AC: 0 AN: 2654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53106

Other (OTH) AF: 0.00 AC: 0 AN: 1497

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000182 AC: 1

ExAC AF: 0.0000249 AC: 3

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.1
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.22
Sift	Benign	0.40	T
Sift4G	Uncertain	0.026	D
Polyphen		1.0	D
Vest4		0.46
MVP		0.86
MPC		0.72
ClinPred		0.52	D
GERP RS		5.6
PromoterAI		0.032	Neutral
Varity_R		0.35
gMVP		0.29
Mutation Taster		=96/4	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs372521943; hg19: chrX-110961132;