chrX-71537869-C-G

Variant names:

• chrX-71537869-C-G
• rs755471023
• NM_181672.3:c.259C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BS1_Supporting BS2

The NM_181672.3(OGT):​c.259C>G​(p.Leu87Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000264 in 1,098,071 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000026 (0 hom. 8 hem.)
• Consequence: OGT NM_181672.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.95
• 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: Likely_benign. The variant received -6 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20782855).
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000264 (29/1098071) while in subpopulation NFE AF = 0.0000344 (29/842022). AF 95% confidence interval is 0.0000242. There are 0 homozygotes in GnomAdExome4. There are 8 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAdExome4 at 8 XL gene

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.259C>G	p.Leu87Val	missense	Exon 3 of 22	NP_858058.1	O15294-1
	OGT	NM_181673.3		c.229C>G	p.Leu77Val	missense	Exon 3 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.259C>G	p.Leu87Val	missense	Exon 3 of 22	ENSP00000362824.3	O15294-1
	OGT	ENST00000373701.7	TSL:1	c.229C>G	p.Leu77Val	missense	Exon 3 of 22	ENSP00000362805.3	O15294-3
	OGT	ENST00000925317.1		c.259C>G	p.Leu87Val	missense	Exon 3 of 22	ENSP00000595376.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000164 AC: 3 AN: 182437 AF XY: 0.0000297

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: 0.0000247

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.0000264 AC: 29 AN: 1098071 Hom.: 0 Cov.: 30 AF XY: 0.0000220 AC XY: 8 AN XY: 363433

African (AFR) AF: 0.00 AC: 0 AN: 26400

American (AMR) AF: 0.00 AC: 0 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 54135

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40491

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

European-Non Finnish (NFE) AF: 0.0000344 AC: 29 AN: 842022

Other (OTH) AF: 0.00 AC: 0 AN: 46093

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.21	T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.0
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.055
Sift	Benign	0.29	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.33
MVP		0.71
MPC		1.4
ClinPred		0.27	T
GERP RS		4.7
Varity_R		0.37
gMVP		0.72
Mutation Taster		=91/9	polymorphism

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: rs755471023; hg19: chrX-70757719;