X-71533327-G-A

Variant names:

• chrX-71533327-G-A
• NM_181672.3:c.28G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_181672.3(OGT):​c.28G>A​(p.Asp10Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000922 in 1,084,068 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: not found (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: 8.49

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.28G>A	p.Asp10Asn	missense_variant	Exon 1 of 22	ENST00000373719.8	NP_858058.1
OGT	NM_181673.3	c.28G>A	p.Asp10Asn	missense_variant	Exon 1 of 22		NP_858059.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OGT	ENST00000373719.8	c.28G>A	p.Asp10Asn	missense_variant	Exon 1 of 22	1	NM_181672.3	ENSP00000362824.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.22e-7 AC: 1 AN: 1084068 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 353404

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000120

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 10, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.29	T;.
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.69	N;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.59	N;N
REVEL	Benign	0.18
Sift	Uncertain	0.010	D;D
Sift4G	Benign	0.29	T;T
Polyphen		0.014	B;D
Vest4		0.52
MutPred		0.30		Gain of MoRF binding (P = 0.0847);Gain of MoRF binding (P = 0.0847);
MVP		0.87
MPC		1.4
ClinPred		0.88	D
GERP RS		5.1
Varity_R		0.39
gMVP		0.75

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-70753177; COSMIC: COSV101035598; COSMIC: COSV101035598;