X-100914653-G-T

Variant names:

• chrX-100914653-G-T
• NM_212559.3:c.1035C>A

Variant summary

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

The NM_212559.3(XKRX):​c.1035C>A​(p.Asn345Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: XKRX NM_212559.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.19

Genes affected

XKRX (HGNC:29845): (XK related X-linked) This gene encodes a protein that is related to a component of the XK/Kell complex of the Kell blood group system. The encoded protein includes several transmembrane domains, is known to be exposed to the cell surface, and may function as a membrane transporter. [provided by RefSeq, May 2010]

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 rank	MANE	Protein	UniProt
XKRX	NM_212559.3	c.1035C>A	p.Asn345Lys	missense_variant	Exon 3 of 3	ENST00000372956.3	NP_997724.2
XKRX	XM_011530954.4	c.1074C>A	p.Asn358Lys	missense_variant	Exon 3 of 4		XP_011529256.1
XKRX	XM_011530955.2	c.687C>A	p.Asn229Lys	missense_variant	Exon 4 of 4		XP_011529257.1
XKRX	XM_017029517.2	c.423C>A	p.Asn141Lys	missense_variant	Exon 2 of 2		XP_016885006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XKRX	ENST00000372956.3	c.1035C>A	p.Asn345Lys	missense_variant	Exon 3 of 3	1	NM_212559.3	ENSP00000362047.2
XKRX	ENST00000468904	c.*346C>A		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000419884.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1035C>A (p.N345K) alteration is located in exon 3 (coding exon 3) of the XKRX gene. This alteration results from a C to A substitution at nucleotide position 1035, causing the asparagine (N) at amino acid position 345 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	0.54
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.9	L
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.26
Sift	Benign	0.066	T
Sift4G	Benign	0.18	T
Polyphen		0.92	P
Vest4		0.56
MutPred		0.60		Gain of methylation at N345 (P = 0.01);
MVP		0.32
MPC		0.51
ClinPred		0.92	D
GERP RS		3.9
Varity_R		0.31
gMVP		0.60

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-100169642;