X-2789703-G-A

Variant names:

• chrX-2789703-G-A
• rs374318565
• NM_001141919.2:c.250G>A

Variant summary

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

The NM_001141919.2(XG):​c.250G>A​(p.Gly84Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,084,096 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 41 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000064 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.00014 (0 hom. 38 hem.)
• Consequence: XG NM_001141919.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.73

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=0.20305276).
• BS2: High Hemizygotes in GnomAd4 at 3 BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XG	NM_001141919.2	c.250G>A	p.Gly84Arg	missense_variant	Exon 5 of 11	ENST00000644266.2	NP_001135391.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XG	ENST00000644266.2	c.250G>A	p.Gly84Arg	missense_variant	Exon 5 of 11		NM_001141919.2	ENSP00000494087.1
XG	ENST00000381174.10	c.250G>A	p.Gly84Arg	missense_variant	Exon 5 of 10	1		ENSP00000370566.5
XG	ENST00000419513.7	c.184G>A	p.Gly62Arg	missense_variant	Exon 3 of 9	1		ENSP00000411004.3
XG	ENST00000509484.3	c.184G>A	p.Gly62Arg	missense_variant	Exon 3 of 8	3		ENSP00000430005.2

Frequencies

GnomAD3 genomes AF: 0.0000635 AC: 7 AN: 110156 Hom.: 0 Cov.: 23 AF XY: 0.0000912 AC XY: 3 AN XY: 32912

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000296 AC: 3 AN: 101478 Hom.: 0 AF XY: 0.0000402 AC XY: 1 AN XY: 24902

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000697

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000140 AC: 136 AN: 973940 Hom.: 0 Cov.: 20 AF XY: 0.000136 AC XY: 38 AN XY: 279478

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: 0.0000825

Gnomad4 NFE exome AF: 0.000169

Gnomad4 OTH exome AF: 0.0000731

GnomAD4 genome AF: 0.0000635 AC: 7 AN: 110156 Hom.: 0 Cov.: 23 AF XY: 0.0000912 AC XY: 3 AN XY: 32912

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000463 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.250G>A (p.G84R) alteration is located in exon 5 (coding exon 5) of the XG gene. This alteration results from a G to A substitution at nucleotide position 250, causing the glycine (G) at amino acid position 84 to be replaced by an arginine (R). 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	0.33
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Benign	0.21	.;.;T;.
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.59	T;T;T;T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	.;.;M;M
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.3	N;D;D;.
REVEL	Benign	0.12
Sift	Uncertain	0.0060	D;D;D;.
Sift4G	Uncertain	0.0080	.;D;D;.
Polyphen		0.99, 0.99	.;.;D;D
Vest4		0.39
MutPred		0.15		.;.;Gain of methylation at G84 (P = 0.0314);Gain of methylation at G84 (P = 0.0314);
MVP		0.095
MPC		0.20
ClinPred		0.62	D
GERP RS		2.3
Varity_R		0.22
gMVP		0.11

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: rs374318565; hg19: chrX-2707744;