22-16784205-A-G

Position:

• chr22-16784205-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001386955.1(XKR3):​c.794T>C​(p.Leu265Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: XKR3 NM_001386955.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.47

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XKR3	NM_001386955.1	c.794T>C	p.Leu265Pro	missense_variant	4/4	ENST00000684488.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XKR3	ENST00000684488.1	c.794T>C	p.Leu265Pro	missense_variant	4/4		NM_001386955.1	P1
XKR3	ENST00000331428.5	c.794T>C	p.Leu265Pro	missense_variant	4/4	1		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461866 Hom.: 0 Cov.: 75 AF XY: 0.00000688 AC XY: 5 AN XY: 727230

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: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 28, 2023

The c.794T>C (p.L265P) alteration is located in exon 4 (coding exon 3) of the XKR3 gene. This alteration results from a T to C substitution at nucleotide position 794, causing the leucine (L) at amino acid position 265 to be replaced by a proline (P). 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	0.31
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	0.97	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.98	D
Vest4		0.51
MutPred		0.67		Loss of stability (P = 0.0174);
MVP		0.61
MPC		4.9
ClinPred		0.95	D
GERP RS		0.77
Varity_R		0.76
gMVP		0.72

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: rs1418060073; hg19: chr22-17265095;