chr22-16799773-C-T

Position:

• chr22-16799773-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001386955.1(XKR3):​c.587G>A​(p.Arg196Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: XKR3 NM_001386955.1 missense, splice_region
• Scores: Splicing: ADA: 0.001166
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.28

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.749

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XKR3	NM_001386955.1	c.587G>A	p.Arg196Lys	missense_variant, splice_region_variant	3/4	ENST00000684488.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XKR3	ENST00000684488.1	c.587G>A	p.Arg196Lys	missense_variant, splice_region_variant	3/4		NM_001386955.1	P1
XKR3	ENST00000331428.5	c.587G>A	p.Arg196Lys	missense_variant, splice_region_variant	3/4	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Jun 30, 2023

The c.587G>A (p.R196K) alteration is located in exon 3 (coding exon 2) of the XKR3 gene. This alteration results from a G to A substitution at nucleotide position 587, causing the arginine (R) at amino acid position 196 to be replaced by a lysine (K). 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	Uncertain	0.38
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.88	N
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.25
Sift	Benign	0.099	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.20
MutPred		0.84		Gain of ubiquitination at R196 (P = 0.0276);
MVP		0.53
MPC		2.8
ClinPred		0.78	D
GERP RS		0.76
Varity_R		0.13
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0012
dbscSNV1_RF	Benign	0.016
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-17280663;