22-16784304-G-C

Variant names:

• chr22-16784304-G-C
• rs9605146
• NM_001386955.1:c.695C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001386955.1(XKR3):​c.695C>G​(p.Pro232Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: XKR3 NM_001386955.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.62
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386955.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XKR3	NM_001386955.1	MANE Select	c.695C>G	p.Pro232Arg	missense	Exon 4 of 4	NP_001373884.1
	XKR3	NM_001318251.3		c.695C>G	p.Pro232Arg	missense	Exon 4 of 4	NP_001305180.1
	XKR3	NM_001386956.1		c.695C>G	p.Pro232Arg	missense	Exon 4 of 4	NP_001373885.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XKR3	ENST00000684488.1	MANE Select	c.695C>G	p.Pro232Arg	missense	Exon 4 of 4	ENSP00000507478.1
	XKR3	ENST00000331428.5	TSL:1	c.695C>G	p.Pro232Arg	missense	Exon 4 of 4	ENSP00000331704.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461818 Hom.: 0 Cov.: 51 AF XY: 0.00000138 AC XY: 1 AN XY: 727210

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111962

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.0064	T
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.6
PROVEAN	Pathogenic	-5.1	D
REVEL	Benign	0.27
Sift	Benign	0.28	T
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.49
MutPred		0.60		Gain of ubiquitination at K229 (P = 0.1181)
MVP		0.46
MPC		3.4
ClinPred		0.89	D
GERP RS		-0.57
Varity_R		0.15
gMVP		0.21
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs9605146; hg19: chr22-17265194;