rs9605146

Positions:

• chr22-16784304-G-A
• chr22-16784304-G-T

Variant summary

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

The NM_001386955.1(XKR3):​c.695C>T​(p.Pro232Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 1,613,668 control chromosomes in the GnomAD database, including 117,528 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.39 (11783 hom., cov: 33)
  • Exomes 𝑓: 0.38 (105745 hom.)
• Consequence: XKR3 NM_001386955.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.62

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=0.0059199333).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.441 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XKR3	NM_001386955.1	c.695C>T	p.Pro232Leu	missense_variant	4/4	ENST00000684488.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XKR3	ENST00000684488.1	c.695C>T	p.Pro232Leu	missense_variant	4/4		NM_001386955.1	P1
XKR3	ENST00000331428.5	c.695C>T	p.Pro232Leu	missense_variant	4/4	1		P1

Frequencies

GnomAD3 genomes AF: 0.388 AC: 59021 AN: 151930 Hom.: 11782 Cov.: 33

Gnomad AFR AF: 0.447

Gnomad AMI AF: 0.366

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.446

Gnomad EAS AF: 0.447

Gnomad SAS AF: 0.398

Gnomad FIN AF: 0.264

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.378

Gnomad OTH AF: 0.401

GnomAD4 exome AF: 0.378 AC: 551915 AN: 1461620 Hom.: 105745 Cov.: 51 AF XY: 0.378 AC XY: 274702 AN XY: 727106

Gnomad4 AFR exome AF: 0.454

Gnomad4 AMR exome AF: 0.220

Gnomad4 ASJ exome AF: 0.441

Gnomad4 EAS exome AF: 0.425

Gnomad4 SAS exome AF: 0.382

Gnomad4 FIN exome AF: 0.275

Gnomad4 NFE exome AF: 0.382

Gnomad4 OTH exome AF: 0.394

GnomAD4 genome AF: 0.388 AC: 59050 AN: 152048 Hom.: 11783 Cov.: 33 AF XY: 0.383 AC XY: 28477 AN XY: 74314

Gnomad4 AFR AF: 0.447

Gnomad4 AMR AF: 0.323

Gnomad4 ASJ AF: 0.446

Gnomad4 EAS AF: 0.447

Gnomad4 SAS AF: 0.398

Gnomad4 FIN AF: 0.264

Gnomad4 NFE AF: 0.378

Gnomad4 OTH AF: 0.399

Alfa AF: 0.389 Hom.: 20910

Bravo AF: 0.393

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	8.4
DANN	Benign	0.91
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	P
PROVEAN	Pathogenic	-5.5	D
REVEL	Benign	0.14
Sift	Benign	0.39	T
Sift4G	Uncertain	0.053	T
Polyphen		0.33	B
Vest4		0.17
MVP		0.23
MPC		3.3
ClinPred		0.25	T
GERP RS		-0.57
Varity_R		0.063
gMVP		0.19

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: rs9605146; hg19: chr22-17265194; COSMIC: COSV105232195;