chr22-16799839-C-A

Position:

• chr22-16799839-C-A

Variant summary

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

The NM_001386955.1(XKR3):​c.521G>T​(p.Gly174Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G174S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: XKR3 NM_001386955.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.363

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.521G>T	p.Gly174Val	missense_variant	3/4	ENST00000684488.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XKR3	ENST00000684488.1	c.521G>T	p.Gly174Val	missense_variant	3/4		NM_001386955.1	P1
XKR3	ENST00000331428.5	c.521G>T	p.Gly174Val	missense_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

Jan 09, 2024

The c.521G>T (p.G174V) alteration is located in exon 3 (coding exon 2) of the XKR3 gene. This alteration results from a G to T substitution at nucleotide position 521, causing the glycine (G) at amino acid position 174 to be replaced by a valine (V). 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	0.25
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0067	T
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N
PROVEAN	Pathogenic	-6.1	D
REVEL	Benign	0.19
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.80	P
Vest4		0.29
MutPred		0.75		Gain of catalytic residue at G174 (P = 0.0741);
MVP		0.33
MPC		0.29
ClinPred		0.91	D
GERP RS		-0.29
Varity_R		0.31
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: chr22-17280729;