Variant X-100914397-T-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_212559.3(XKRX):c.1291A>T(p.Thr431Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000019 in 1,209,957 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000019 ( 0 hom. 4 hem. )

Consequence

XKRX
NM_212559.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.19

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.035095483).

BS2

High Hemizygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XKRX	NM_212559.3 linkuse as main transcript	c.1291A>T	p.Thr431Ser	missense_variant	3/3	ENST00000372956.3	NP_997724.2	Q6PP77-1
XKRX	XM_011530955.2 linkuse as main transcript	c.943A>T	p.Thr315Ser	missense_variant	4/4		XP_011529257.1
XKRX	XM_017029517.2 linkuse as main transcript	c.679A>T	p.Thr227Ser	missense_variant	2/2		XP_016885006.1	Q6PP77-2
XKRX	XM_011530954.4 linkuse as main transcript	c.1106+224A>T		intron_variant			XP_011529256.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XKRX	ENST00000372956.3 linkuse as main transcript	c.1291A>T	p.Thr431Ser	missense_variant	3/3	1	NM_212559.3	ENSP00000362047.2		Q6PP77-1
XKRX	ENST00000468904.1 linkuse as main transcript	c.*602A>T		3_prime_UTR_variant	2/2	2		ENSP00000419884.1		C9JYI8

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111919

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34117

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.000664

GnomAD3 exomes

AF:

0.0000273

AC:

AN:

183276

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67752

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000109

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:

0.0000245

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000191

AC:

AN:

1098038

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

363392

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000568

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:

0.0000190

Gnomad4 OTH exome

AF:

0.0000651

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111919

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34117

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:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.000664

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000330

AC:

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 13, 2023

The c.1291A>T (p.T431S) alteration is located in exon 3 (coding exon 3) of the XKRX gene. This alteration results from a A to T substitution at nucleotide position 1291, causing the threonine (T) at amino acid position 431 to be replaced by a serine (S). 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

0.064

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.075

DANN

Benign

0.67

DEOGEN2

Benign

0.0017

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.31

M_CAP

Benign

0.023

MetaRNN

Benign

0.035

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

PrimateAI

Benign

0.28

PROVEAN

Benign

0.39

REVEL

Benign

0.043

Sift

Benign

0.75

Sift4G

Benign

0.76

Polyphen

0.0

Vest4

0.060

MutPred

0.16

Gain of disorder (P = 0.0431);

MVP

0.040

MPC

0.087

ClinPred

0.023

GERP RS

0.99

Varity_R

0.036

gMVP

0.26

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