rs1131692155

Variant names:

• chrX-71555223-G-C
• rs1131692155
• NM_181672.3:c.762G>C

Your query was ambiguous. Multiple possible variants found:

• chrX-71555223-G-C
• chrX-71555223-G-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS1 PM2 PP2 PP3_Moderate PP5

The NM_181672.3(OGT):​c.762G>C​(p.Leu254Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 21)
• Consequence: OGT NM_181672.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.70
• Publications: 17 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, ClinGen, Illumina, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS1: Transcript NM_181672.3 (OGT) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.861
• PP5: Variant X-71555223-G-C is Pathogenic according to our data. Variant chrX-71555223-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 804282.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OGT	NM_181672.3	c.762G>C	p.Leu254Phe	missense_variant	Exon 7 of 22	ENST00000373719.8	NP_858058.1
OGT	NM_181673.3	c.732G>C	p.Leu244Phe	missense_variant	Exon 7 of 22		NP_858059.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OGT	ENST00000373719.8	c.762G>C	p.Leu254Phe	missense_variant	Exon 7 of 22	1	NM_181672.3	ENSP00000362824.3

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual disability, X-linked 106 Pathogenic:1

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Daan van Aalten Lab, University of Dundee

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	-0.086	T
MutationAssessor	Benign	0.90	L;.
PhyloP100		2.7
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.2	D;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.015	D;D
Polyphen		1.0	D;D
Vest4		0.67
MutPred		0.52		Loss of helix (P = 0.1706);.;
MVP		0.94
MPC		2.8
ClinPred		0.98	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.93
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1131692155; hg19: chrX-70775073;