X-71537959-C-T

Variant names:

• chrX-71537959-C-T
• rs1317050680
• NM_181672.3:c.349C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2

The NM_181672.3(OGT):​c.349C>T​(p.Arg117Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000546 in 1,098,040 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000055 (0 hom. 1 hem.)
• Consequence: OGT NM_181672.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.84

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP2: Missense variant in the OGT gene, where missense mutations are typically associated with disease (based on misZ statistic). 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). GenCC associations: The gene is linked to intellectual disability, X-linked 106.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OGT	NM_181672.3	c.349C>T	p.Arg117Cys	missense_variant	Exon 3 of 22	ENST00000373719.8	NP_858058.1
OGT	NM_181673.3	c.319C>T	p.Arg107Cys	missense_variant	Exon 3 of 22		NP_858059.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OGT	ENST00000373719.8	c.349C>T	p.Arg117Cys	missense_variant	Exon 3 of 22	1	NM_181672.3	ENSP00000362824.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000545 AC: 1 AN: 183425 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67869

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000546 AC: 6 AN: 1098040 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 1 AN XY: 363398

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000475

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, X-linked 106 Uncertain:1

Apr 27, 2019

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Dec 18, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.76	D;.;T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.72	D;D;D
MetaSVM	Uncertain	0.015	D
MutationAssessor	Uncertain	2.6	M;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-4.2	D;D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.66
MutPred		0.53		Gain of catalytic residue at L118 (P = 0.0066);.;.;
MVP		0.86
MPC		3.1
ClinPred		0.92	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs1317050680; hg19: chrX-70757809; COSMIC: COSV65480922; COSMIC: COSV65480922;