X-100914577-C-T

Variant names:

• chrX-100914577-C-T
• rs745641321
• NM_212559.3:c.1111G>A

Variant summary

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

The NM_212559.3(XKRX):​c.1111G>A​(p.Gly371Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000455 in 1,098,232 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 2 hem.)
• Consequence: XKRX NM_212559.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.95

Genes affected

XKRX (HGNC:29845): (XK related X-linked) This gene encodes a protein that is related to a component of the XK/Kell complex of the Kell blood group system. The encoded protein includes several transmembrane domains, is known to be exposed to the cell surface, and may function as a membrane transporter. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22586757).
• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XKRX	NM_212559.3	c.1111G>A	p.Gly371Arg	missense_variant	Exon 3 of 3	ENST00000372956.3	NP_997724.2
XKRX	XM_011530955.2	c.763G>A	p.Gly255Arg	missense_variant	Exon 4 of 4		XP_011529257.1
XKRX	XM_017029517.2	c.499G>A	p.Gly167Arg	missense_variant	Exon 2 of 2		XP_016885006.1
XKRX	XM_011530954.4	c.1106+44G>A		intron_variant	Intron 3 of 3		XP_011529256.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XKRX	ENST00000372956.3	c.1111G>A	p.Gly371Arg	missense_variant	Exon 3 of 3	1	NM_212559.3	ENSP00000362047.2
XKRX	ENST00000468904	c.*422G>A		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000419884.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000455 AC: 5 AN: 1098232 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 2 AN XY: 363588

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: 0.00000594

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1111G>A (p.G371R) alteration is located in exon 3 (coding exon 3) of the XKRX gene. This alteration results from a G to A substitution at nucleotide position 1111, causing the glycine (G) at amino acid position 371 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	Uncertain	0.45
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0062	T
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.55	N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.25
Sift	Benign	0.55	T
Sift4G	Benign	0.71	T
Polyphen		0.98	D
Vest4		0.19
MutPred		0.51		Gain of MoRF binding (P = 0.0196);
MVP		0.51
MPC		0.55
ClinPred		0.76	D
GERP RS		4.9
Varity_R		0.19
gMVP		0.47

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: rs745641321; hg19: chrX-100169566;