rs5748648

Positions:

• chr22-16799932-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001386955.1(XKR3):​c.428C>T​(p.Thr143Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0736 in 1,613,818 control chromosomes in the GnomAD database, including 6,010 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.11 (1282 hom., cov: 32)
  • Exomes 𝑓: 0.070 (4728 hom.)
• Consequence: XKR3 NM_001386955.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.319

Genes affected

XKR3 (HGNC:28778): (XK related 3) XKRX (MIM 300684) and XKR3 are homologs of the Kell blood group precursor XK (MIM 314850), which is a putative membrane transporter and a component of the XK/Kell complex of the Kell blood group system (Calenda et al., 2006 [PubMed 16431037]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0040911734).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XKR3	NM_001386955.1	c.428C>T	p.Thr143Met	missense_variant	3/4	ENST00000684488.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XKR3	ENST00000684488.1	c.428C>T	p.Thr143Met	missense_variant	3/4		NM_001386955.1	P1
XKR3	ENST00000331428.5	c.428C>T	p.Thr143Met	missense_variant	3/4	1		P1

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16537 AN: 151962 Hom.: 1281 Cov.: 32

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.0694

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.0545

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.0398

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0566

Gnomad OTH AF: 0.105

GnomAD3 exomes AF: 0.0953 AC: 23750 AN: 249330 Hom.: 1539 AF XY: 0.0933 AC XY: 12621 AN XY: 135260

Gnomad AFR exome AF: 0.216

Gnomad AMR exome AF: 0.161

Gnomad ASJ exome AF: 0.0571

Gnomad EAS exome AF: 0.108

Gnomad SAS exome AF: 0.143

Gnomad FIN exome AF: 0.0443

Gnomad NFE exome AF: 0.0573

Gnomad OTH exome AF: 0.0886

GnomAD4 exome AF: 0.0699 AC: 102241 AN: 1461738 Hom.: 4728 Cov.: 31 AF XY: 0.0714 AC XY: 51917 AN XY: 727152

Gnomad4 AFR exome AF: 0.221

Gnomad4 AMR exome AF: 0.154

Gnomad4 ASJ exome AF: 0.0531

Gnomad4 EAS exome AF: 0.0940

Gnomad4 SAS exome AF: 0.144

Gnomad4 FIN exome AF: 0.0468

Gnomad4 NFE exome AF: 0.0560

Gnomad4 OTH exome AF: 0.0837

GnomAD4 genome AF: 0.109 AC: 16556 AN: 152080 Hom.: 1282 Cov.: 32 AF XY: 0.108 AC XY: 8016 AN XY: 74344

Gnomad4 AFR AF: 0.213

Gnomad4 AMR AF: 0.114

Gnomad4 ASJ AF: 0.0545

Gnomad4 EAS AF: 0.103

Gnomad4 SAS AF: 0.143

Gnomad4 FIN AF: 0.0398

Gnomad4 NFE AF: 0.0566

Gnomad4 OTH AF: 0.104

Alfa AF: 0.0700 Hom.: 1033

Bravo AF: 0.119

TwinsUK AF: 0.0618 AC: 229

ALSPAC AF: 0.0501 AC: 193

ESP6500AA AF: 0.196 AC: 742

ESP6500EA AF: 0.0569 AC: 470

ExAC AF: 0.0950 AC: 11486

Asia WGS AF: 0.130 AC: 451 AN: 3478

EpiCase AF: 0.0582

EpiControl AF: 0.0597

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	10
DANN	Uncertain	0.97
DEOGEN2	Benign	0.0061	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0098	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	P
PROVEAN	Benign	0.27	N
REVEL	Benign	0.078
Sift	Benign	0.11	T
Sift4G	Benign	0.10	T
Polyphen		0.021	B
Vest4		0.024
MPC		0.093
ClinPred		0.013	T
GERP RS		-1.5
Varity_R		0.016
gMVP		0.074

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: rs5748648; hg19: chr22-17280822; COSMIC: COSV58888372;