8-55523796-A-G

Position:

• chr8-55523796-A-G

Variant summary

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

The NM_052898.2(XKR4):​c.1522A>G​(p.Met508Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: XKR4 NM_052898.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

Genes affected

XKR4 (HGNC:29394): (XK related 4) Enables phospholipid scramblase activity. Involved in phosphatidylserine exposure on apoptotic cell surface. Predicted to be integral component of membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

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
XKR4	NM_052898.2	c.1522A>G	p.Met508Val	missense_variant	3/3	ENST00000327381.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XKR4	ENST00000327381.7	c.1522A>G	p.Met508Val	missense_variant	3/3	1	NM_052898.2	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

Aug 10, 2021

The c.1522A>G (p.M508V) alteration is located in exon 3 (coding exon 3) of the XKR4 gene. This alteration results from a A to G substitution at nucleotide position 1522, causing the methionine (M) at amino acid position 508 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	0.23
BayesDel_addAF	Benign	-0.0018	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.026	T;T
Eigen	Benign	0.0030
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	.;T
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.050	N;N
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.12	N;.
REVEL	Benign	0.19
Sift	Benign	0.82	T;.
Sift4G	Benign	0.95	T;T
Polyphen		0.28	B;B
Vest4		0.82
MutPred		0.41		Gain of catalytic residue at M508 (P = 0.05);Gain of catalytic residue at M508 (P = 0.05);
MVP		0.39
MPC		1.6
ClinPred		0.77	D
GERP RS		5.8
Varity_R		0.27
gMVP		0.75

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: chr8-56436355; COSMIC: COSV59309189; COSMIC: COSV59309189;