X-100914916-G-C

Variant names:

• chrX-100914916-G-C
• NM_212559.3:c.772C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_212559.3(XKRX):​c.772C>G​(p.Leu258Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000728 in 1,098,228 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic 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. L258Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000073 (0 hom. 1 hem.)
• Consequence: XKRX NM_212559.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.33
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.751

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_212559.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XKRX	NM_212559.3	MANE Select	c.772C>G	p.Leu258Val	missense	Exon 3 of 3	NP_997724.2	Q6PP77-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XKRX	ENST00000372956.3	TSL:1 MANE Select	c.772C>G	p.Leu258Val	missense	Exon 3 of 3	ENSP00000362047.2	Q6PP77-1
	XKRX	ENST00000468904.1	TSL:2	c.*83C>G		3_prime_UTR	Exon 2 of 2	ENSP00000419884.1	C9JYI8

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000728 AC: 8 AN: 1098228 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363584

African (AFR) AF: 0.00 AC: 0 AN: 26403

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54149

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00000950 AC: 8 AN: 842113

Other (OTH) AF: 0.00 AC: 0 AN: 46098

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.3
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.95	P
Vest4		0.73
MutPred		0.78		Loss of stability (P = 0.1789)
MVP		0.21
MPC		0.51
ClinPred		0.97	D
GERP RS		2.8
Varity_R		0.84
gMVP		0.72
Mutation Taster		=51/49	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

hg19: chrX-100169905;