chrX-71533333-A-C

Variant names:

• chrX-71533333-A-C
• rs1246539337
• NM_181672.3:c.34A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_181672.3(OGT):​c.34A>C​(p.Thr12Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000167 in 1,194,317 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: OGT NM_181672.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.92
• Publications: 0 publications found

Genes affected

OGT (HGNC:8127): (O-linked N-acetylglucosamine (GlcNAc) transferase) This gene encodes a glycosyltransferase that catalyzes the addition of a single N-acetylglucosamine in O-glycosidic linkage to serine or threonine residues. Since both phosphorylation and glycosylation compete for similar serine or threonine residues, the two processes may compete for sites, or they may alter the substrate specificity of nearby sites by steric or electrostatic effects. The protein contains multiple tetratricopeptide repeats that are required for optimal recognition of substrates. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

OGT Gene-Disease associations (from GenCC):

• intellectual disability, X-linked 106

  Inheritance: XL Classification: STRONG, MODERATE Submitted by: G2P, Illumina, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 5.6667 (above the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, X-linked 106.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181672.3. 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
	OGT	NM_181672.3	MANE Select	c.34A>C	p.Thr12Pro	missense	Exon 1 of 22	NP_858058.1	O15294-1
	OGT	NM_181673.3		c.34A>C	p.Thr12Pro	missense	Exon 1 of 22	NP_858059.1	O15294-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OGT	ENST00000373719.8	TSL:1 MANE Select	c.34A>C	p.Thr12Pro	missense	Exon 1 of 22	ENSP00000362824.3	O15294-1
	OGT	ENST00000373701.7	TSL:1	c.34A>C	p.Thr12Pro	missense	Exon 1 of 22	ENSP00000362805.3	O15294-3
	OGT	ENST00000925317.1		c.34A>C	p.Thr12Pro	missense	Exon 1 of 22	ENSP00000595376.1

Frequencies

GnomAD3 genomes AF: 0.00000900 AC: 1 AN: 111161 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000328

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

GnomAD4 exome AF: 9.23e-7 AC: 1 AN: 1083156 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 352912

African (AFR) AF: 0.0000383 AC: 1 AN: 26076

American (AMR) AF: 0.00 AC: 0 AN: 33572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19097

East Asian (EAS) AF: 0.00 AC: 0 AN: 29323

South Asian (SAS) AF: 0.00 AC: 0 AN: 51747

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39527

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 834198

Other (OTH) AF: 0.00 AC: 0 AN: 45501

GnomAD4 genome AF: 0.00000900 AC: 1 AN: 111161 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33345

African (AFR) AF: 0.0000328 AC: 1 AN: 30523

American (AMR) AF: 0.00 AC: 0 AN: 10505

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3551

South Asian (SAS) AF: 0.00 AC: 0 AN: 2556

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6012

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52950

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

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Intellectual disability, X-linked 106 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.54	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.1	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.47	N
REVEL	Uncertain	0.50
Sift	Benign	0.032	D
Sift4G	Benign	0.13	T
Polyphen		0.95	P
Vest4		0.53
MutPred		0.37		Gain of relative solvent accessibility (P = 0.0289)
MVP		0.97
MPC		1.8
ClinPred		0.91	D
GERP RS		5.1
PromoterAI		-0.080	Neutral
Varity_R		0.47
gMVP		0.73
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1246539337; hg19: chrX-70753183;