X-2794555-C-T

Variant names:

• chrX-2794555-C-T
• rs755612535
• NM_001141919.2:c.274C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001141919.2(XG):​c.274C>T​(p.Arg92Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000729 in 1,097,594 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 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: 24)
  • Exomes 𝑓: 0.0000073 (0 hom. 3 hem.)
• Consequence: XG NM_001141919.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.155
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10046309).
• BS2: High Hemizygotes in GnomAdExome4 at 3 BG gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001141919.2. 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
	XG	NM_001141919.2	MANE Select	c.274C>T	p.Arg92Cys	missense	Exon 6 of 11	NP_001135391.1	P55808-3
	XG	NM_001141920.2		c.277C>T	p.Arg93Cys	missense	Exon 6 of 10	NP_001135392.1	P55808-2
	XG	NM_175569.3		c.274C>T	p.Arg92Cys	missense	Exon 6 of 10	NP_780778.1	P55808-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XG	ENST00000644266.2	MANE Select	c.274C>T	p.Arg92Cys	missense	Exon 6 of 11	ENSP00000494087.1	P55808-3
	XG	ENST00000381174.10	TSL:1	c.274C>T	p.Arg92Cys	missense	Exon 6 of 10	ENSP00000370566.5	P55808-1
	XG	ENST00000419513.7	TSL:1	c.208C>T	p.Arg70Cys	missense	Exon 4 of 9	ENSP00000411004.3	A0A2U3U020

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.0000277 AC: 5 AN: 180550 AF XY: 0.0000460

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000371

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000729 AC: 8 AN: 1097594 Hom.: 0 Cov.: 30 AF XY: 0.00000827 AC XY: 3 AN XY: 362974

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26375

American (AMR) AF: 0.0000285 AC: 1 AN: 35146

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19375

East Asian (EAS) AF: 0.00 AC: 0 AN: 30135

South Asian (SAS) AF: 0.0000741 AC: 4 AN: 54007

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40497

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4134

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841863

Other (OTH) AF: 0.00 AC: 0 AN: 46062

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00536222), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 24

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.16	T
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.15
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.020
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.070	T
Polyphen		0.99	D
Vest4		0.21
MutPred		0.18		Gain of sheet (P = 0.0827)
MVP		0.072
MPC		0.60
ClinPred		0.36	T
GERP RS		1.9
Varity_R		0.17
gMVP		0.11
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs755612535; hg19: chrX-2712596;