X-2814366-C-T

Position:

• chrX-2814366-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001141919.2(XG):​c.574C>T​(p.Pro192Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000458 in 1,091,009 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 2 hem.)
• Consequence: XG NM_001141919.2 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.36

Genes affected

XG (HGNC:12806): (Xg glycoprotein (Xg blood group)) This gene encodes the XG blood group antigen, and is located at the pseudoautosomal boundary on the short (p) arm of chromosome X. The three 5' exons reside in the pseudoautosomal region and the remaining exons within the X-specific end. A truncated copy of this gene is found on the Y chromosome at the pseudoautosomal boundary. It is transcribed, but not expected to make a Y-chromosome specific gene product. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12060264).
• BS2: High Hemizygotes in GnomAdExome4 at 2 BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XG	NM_001141919.2	c.574C>T	p.Pro192Ser	missense_variant, splice_region_variant	11/11	ENST00000644266.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XG	ENST00000644266.2	c.574C>T	p.Pro192Ser	missense_variant, splice_region_variant	11/11		NM_001141919.2
XG	ENST00000381174.10	c.529C>T	p.Pro177Ser	missense_variant, splice_region_variant	10/10	1		P1
XG	ENST00000419513.7	c.508C>T	p.Pro170Ser	missense_variant, splice_region_variant	9/9	1
XG	ENST00000509484.3	c.463C>T	p.Pro155Ser	missense_variant, splice_region_variant	8/8	3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000458 AC: 5 AN: 1091009 Hom.: 0 Cov.: 30 AF XY: 0.00000559 AC XY: 2 AN XY: 357689

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: 0.00000357

Gnomad4 OTH exome AF: 0.0000437

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2023

The c.574C>T (p.P192S) alteration is located in exon 11 (coding exon 11) of the XG gene. This alteration results from a C to T substitution at nucleotide position 574, causing the proline (P) at amino acid position 192 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	17
DANN	Uncertain	0.99
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.58	T;T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.36	T
REVEL	Benign	0.070
Polyphen		1.0	.;.;D;D
Vest4		0.23
MutPred		0.14		.;.;Loss of glycosylation at T174 (P = 0.1062);.;
MVP		0.12
MPC		0.44
ClinPred		0.61	D
GERP RS		1.1
Varity_R		0.037
gMVP		0.093

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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-2732407;