Genetic Variant XKRX:p.Arg305Gln (chrX-100914774-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_212559.3(XKRX):c.914G>A(p.Arg305Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,209,668 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 47 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.00012 ( 0 hom. 44 hem. )

Consequence

XKRX
NM_212559.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.29

Variant links:

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]

XKRX links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020036638).

BS2

High Hemizygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XKRX	NM_212559.3 link	c.914G>A	p.Arg305Gln	missense_variant	Exon 3 of 3	ENST00000372956.3	NP_997724.2	Q6PP77-1
XKRX	XM_011530954.4 link	c.953G>A	p.Arg318Gln	missense_variant	Exon 3 of 4		XP_011529256.1
XKRX	XM_011530955.2 link	c.566G>A	p.Arg189Gln	missense_variant	Exon 4 of 4		XP_011529257.1
XKRX	XM_017029517.2 link	c.302G>A	p.Arg101Gln	missense_variant	Exon 2 of 2		XP_016885006.1	Q6PP77-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XKRX	ENST00000372956.3 link	c.914G>A	p.Arg305Gln	missense_variant	Exon 3 of 3	1	NM_212559.3	ENSP00000362047.2		Q6PP77-1
XKRX	ENST00000468904 link	c.*225G>A		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000419884.1		C9JYI8

Frequencies

GnomAD3 genomes

AF:

0.000144

AC:

AN:

111388

Hom.:

Cov.:

AF XY:

0.0000893

AC XY:

AN XY:

33586

show subpopulations

Gnomad AFR

AF:

0.000196

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000479

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000282

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000335

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000262

AC:

AN:

183372

Hom.:

AF XY:

0.000192

AC XY:

AN XY:

67840

show subpopulations

Gnomad AFR exome

AF:

0.000380

Gnomad AMR exome

AF:

0.000328

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000938

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00106

Gnomad NFE exome

AF:

0.0000244

Gnomad OTH exome

AF:

0.000442

GnomAD4 exome

AF:

0.000116

AC:

127

AN:

1098227

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

363581

show subpopulations

Gnomad4 AFR exome

AF:

0.000151

Gnomad4 AMR exome

AF:

0.000426

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00103

Gnomad4 SAS exome

AF:

0.000129

Gnomad4 FIN exome

AF:

0.000864

Gnomad4 NFE exome

AF:

0.0000368

Gnomad4 OTH exome

AF:

0.0000868

GnomAD4 genome

AF:

0.000144

AC:

AN:

111441

Hom.:

Cov.:

AF XY:

0.0000892

AC XY:

AN XY:

33649

show subpopulations

Gnomad4 AFR

AF:

0.000196

Gnomad4 AMR

AF:

0.000478

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000283

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000335

Gnomad4 NFE

AF:

0.0000376

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000121

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000222

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 27, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.914G>A (p.R305Q) 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 914, causing the arginine (R) at amino acid position 305 to be replaced by a glutamine (Q). 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

0.12

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.59

M_CAP

Benign

0.012

MetaRNN

Benign

0.020

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.4

REVEL

Benign

0.069

Sift

Benign

0.061

Sift4G

Benign

0.29

Polyphen

0.12

Vest4

0.065

MVP

0.085

MPC

0.11

ClinPred

0.0079

GERP RS

1.9

Varity_R

0.069

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over