chrX-100914880-C-T

Variant names:

• chrX-100914880-C-T
• NM_212559.3:c.808G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_212559.3(XKRX):​c.808G>A​(p.Val270Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000082 in 1,098,221 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000082 (0 hom. 3 hem.)
• Consequence: XKRX NM_212559.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.71

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14504778).
• BS2: High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XKRX	NM_212559.3	c.808G>A	p.Val270Met	missense_variant	Exon 3 of 3	ENST00000372956.3	NP_997724.2
XKRX	XM_011530954.4	c.847G>A	p.Val283Met	missense_variant	Exon 3 of 4		XP_011529256.1
XKRX	XM_011530955.2	c.460G>A	p.Val154Met	missense_variant	Exon 4 of 4		XP_011529257.1
XKRX	XM_017029517.2	c.196G>A	p.Val66Met	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.808G>A	p.Val270Met	missense_variant	Exon 3 of 3	1	NM_212559.3	ENSP00000362047.2
XKRX	ENST00000468904	c.*119G>A		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000419884.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000820 AC: 9 AN: 1098221 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 3 AN XY: 363575

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

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: 0.00000831

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.808G>A (p.V270M) alteration is located in exon 3 (coding exon 3) of the XKRX gene. This alteration results from a G to A substitution at nucleotide position 808, causing the valine (V) at amino acid position 270 to be replaced by a methionine (M). 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	0.14
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.023	T
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.97	L
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.12
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.043	D
Polyphen		0.041	B
Vest4		0.27
MutPred		0.54		Gain of ubiquitination at K268 (P = 0.1181);
MVP		0.23
MPC		0.17
ClinPred		0.43	T
GERP RS		2.5
Varity_R		0.16
gMVP		0.21

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-100169869;