X-37694383-T-C

Position:

chrX-37694383-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2

The NM_021083.4(XK):c.343T>C(p.Ser115Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,206,247 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 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., 1 hem., cov: 23)

Exomes 𝑓: 0.000041 ( 0 hom. 13 hem. )

Consequence

XK
NM_021083.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.83

Variant links:

Genes affected

XK (HGNC:12811): (X-linked Kx blood group antigen, Kell and VPS13A binding protein) This locus controls the synthesis of the Kell blood group 'precursor substance' (Kx). Mutations in this gene have been associated with McLeod syndrome, an X-linked, recessive disorder characterized by abnormalities in the neuromuscular and hematopoietic systems. The encoded protein has structural characteristics of prokaryotic and eukaryotic membrane transport proteins. [provided by RefSeq, Jul 2008]

XK links:

ENSG00000250349 (HGNC:):

ENSG00000250349 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity XK_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.31437457).

BS2

High Hemizygotes in GnomAdExome4 at 13 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XK	NM_021083.4 linkuse as main transcript	c.343T>C	p.Ser115Pro	missense_variant	2/3	ENST00000378616.5	NP_066569.1	P51811
XK	XM_011543978.4 linkuse as main transcript	c.343T>C	p.Ser115Pro	missense_variant	2/3		XP_011542280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XK	ENST00000378616.5 linkuse as main transcript	c.343T>C	p.Ser115Pro	missense_variant	2/3	1	NM_021083.4	ENSP00000367879.3		P51811
ENSG00000250349	ENST00000465127.1 linkuse as main transcript	c.171+268383T>C		intron_variant		5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

112032

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34202

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:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000411

AC:

AN:

1094215

Hom.:

Cov.:

AF XY:

0.0000361

AC XY:

AN XY:

359905

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:

0.00

Gnomad4 NFE exome

AF:

0.0000524

Gnomad4 OTH exome

AF:

0.0000218

GnomAD4 genome

AF:

0.0000179

AC:

AN:

112032

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34202

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:

0.0000376

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2020	Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 18, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt XK protein function. ClinVar contains an entry for this variant (Variation ID: 1303649). This variant has not been reported in the literature in individuals affected with XK-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 115 of the XK protein (p.Ser115Pro). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.070

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.73

M_CAP

Benign

0.068

MetaRNN

Benign

0.31

MetaSVM

Benign

-0.42

MutationAssessor

Uncertain

2.3

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.6

REVEL

Benign

0.28

Sift

Benign

0.077

Sift4G

Benign

0.082

Polyphen

0.97

Vest4

0.30

MutPred

0.28

Loss of phosphorylation at S115 (P = 0.0308);

MVP

0.88

MPC

1.9

ClinPred

0.91

GERP RS

4.8

Varity_R

0.47

gMVP

0.71

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