chrX-111759915-A-T

Variant names:

• chrX-111759915-A-T
• rs761412613
• NM_001099922.3:c.3330A>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001099922.3(ALG13):​c.3330A>T​(p.Gln1110His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000257 in 1,208,464 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q1110Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000026 (0 hom. 8 hem.)
• Consequence: ALG13 NM_001099922.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.718
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.037947983).
• BP6: Variant X-111759915-A-T is Benign according to our data. Variant chrX-111759915-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1730312.
• BS2: High Hemizygotes in GnomAdExome4 at 8 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.3330A>T	p.Gln1110His	missense	Exon 27 of 27	NP_001093392.1	Q9NP73-1
	ALG13	NM_001257231.2		c.3096A>T	p.Gln1032His	missense	Exon 27 of 27	NP_001244160.1	Q9NP73-3
	ALG13	NM_001324292.2		c.3093A>T	p.Gln1031His	missense	Exon 26 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.3330A>T	p.Gln1110His	missense	Exon 27 of 27	ENSP00000378260.3	Q9NP73-1
	ALG13	ENST00000927365.1		c.3306A>T	p.Gln1102His	missense	Exon 27 of 27	ENSP00000597424.1
	ALG13	ENST00000927366.1		c.3156A>T	p.Gln1052His	missense	Exon 25 of 25	ENSP00000597425.1

Frequencies

GnomAD3 genomes AF: 0.0000181 AC: 2 AN: 110677 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000284

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000168 AC: 3 AN: 178644 AF XY: 0.0000301

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: 0.0000381

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000264 AC: 29 AN: 1097734 Hom.: 0 Cov.: 30 AF XY: 0.0000220 AC XY: 8 AN XY: 363238

African (AFR) AF: 0.00 AC: 0 AN: 26397

American (AMR) AF: 0.00 AC: 0 AN: 35139

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

East Asian (EAS) AF: 0.00 AC: 0 AN: 30181

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54097

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40505

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.0000309 AC: 26 AN: 841830

Other (OTH) AF: 0.0000434 AC: 2 AN: 46067

GnomAD4 genome AF: 0.0000181 AC: 2 AN: 110730 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 32964

African (AFR) AF: 0.00 AC: 0 AN: 30471

American (AMR) AF: 0.00 AC: 0 AN: 10304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2636

East Asian (EAS) AF: 0.000285 AC: 1 AN: 3504

South Asian (SAS) AF: 0.00 AC: 0 AN: 2589

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5892

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 52938

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000166 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.000119

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)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	2.7
DANN	Benign	0.85
DEOGEN2	Benign	0.29	T
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.72
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.028
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.0010	B
Vest4		0.076
MutPred		0.24		Loss of sheet (P = 0.1158)
MVP		0.18
MPC		0.16
ClinPred		0.030	T
GERP RS		-6.0
PromoterAI		0.0017	Neutral
Varity_R		0.13
gMVP		0.46
Mutation Taster		=98/2	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs761412613; hg19: chrX-111003143;