Variant X-100914780-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_212559.3(XKRX):c.908T>G(p.Phe303Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000225 in 1,209,759 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 86 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., 7 hem., cov: 23)

Exomes 𝑓: 0.00023 ( 0 hom. 79 hem. )

Consequence

XKRX
NM_212559.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.95

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 Likely_benign. Variant got -4 ACMG points.

BS2

High Hemizygotes in GnomAd4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XKRX	NM_212559.3 linkuse as main transcript	c.908T>G	p.Phe303Cys	missense_variant	3/3	ENST00000372956.3	NP_997724.2	Q6PP77-1
XKRX	XM_011530954.4 linkuse as main transcript	c.947T>G	p.Phe316Cys	missense_variant	3/4		XP_011529256.1
XKRX	XM_011530955.2 linkuse as main transcript	c.560T>G	p.Phe187Cys	missense_variant	4/4		XP_011529257.1
XKRX	XM_017029517.2 linkuse as main transcript	c.296T>G	p.Phe99Cys	missense_variant	2/2		XP_016885006.1	Q6PP77-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XKRX	ENST00000372956.3 linkuse as main transcript	c.908T>G	p.Phe303Cys	missense_variant	3/3	1	NM_212559.3	ENSP00000362047.2		Q6PP77-1
XKRX	ENST00000468904.1 linkuse as main transcript	c.*219T>G		3_prime_UTR_variant	2/2	2		ENSP00000419884.1		C9JYI8

Frequencies

GnomAD3 genomes

AF:

0.000179

AC:

AN:

111515

Hom.:

Cov.:

AF XY:

0.000208

AC XY:

AN XY:

33697

show subpopulations

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:

0.000498

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000320

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000267

AC:

AN:

183382

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

67848

show subpopulations

Gnomad AFR exome

AF:

0.0000760

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:

0.000875

Gnomad NFE exome

AF:

0.000391

Gnomad OTH exome

AF:

0.000442

GnomAD4 exome

AF:

0.000229

AC:

252

AN:

1098244

Hom.:

Cov.:

AF XY:

0.000217

AC XY:

AN XY:

363598

show subpopulations

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:

0.00101

Gnomad4 NFE exome

AF:

0.000241

Gnomad4 OTH exome

AF:

0.000174

GnomAD4 genome

AF:

0.000179

AC:

AN:

111515

Hom.:

Cov.:

AF XY:

0.000208

AC XY:

AN XY:

33697

show subpopulations

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:

0.000498

Gnomad4 NFE

AF:

0.000320

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000260

Hom.:

Bravo

AF:

0.000121

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000280

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2023

The c.908T>G (p.F303C) alteration is located in exon 3 (coding exon 3) of the XKRX gene. This alteration results from a T to G substitution at nucleotide position 908, causing the phenylalanine (F) at amino acid position 303 to be replaced by a cysteine (C). 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

Pathogenic

0.95

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.26

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.092

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.77

M_CAP

Pathogenic

0.74

MetaRNN

Uncertain

0.48

MetaSVM

Benign

-0.36

MutationAssessor

Benign

1.8

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.58

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0090

Polyphen

1.0

Vest4

0.69

MVP

0.30

MPC

0.36

ClinPred

0.16

GERP RS

5.7

Varity_R

0.57

gMVP

0.67

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