chr1-27966605-G-A

Position:

• chr1-27966605-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018053.4(XKR8):​c.593G>A​(p.Gly198Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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: XKR8 NM_018053.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00100

Genes affected

XKR8 (HGNC:25508): (XK related 8) Enables phospholipid scramblase activity. Involved in engulfment of apoptotic cell; phosphatidylserine exposure on apoptotic cell surface; and positive regulation of myoblast differentiation. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

XKR8 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18334523).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XKR8	NM_018053.4	c.593G>A	p.Gly198Asp	missense_variant	3/3	ENST00000373884.6	NP_060523.2
XKR8	XM_011541679.4	c.755G>A	p.Gly252Asp	missense_variant	5/5		XP_011539981.1
XKR8	XM_011541680.4	c.647G>A	p.Gly216Asp	missense_variant	4/4		XP_011539982.1
XKR8	XM_047423826.1	c.592G>A	p.Ala198Thr	missense_variant	4/4		XP_047279782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XKR8	ENST00000373884.6	c.593G>A	p.Gly198Asp	missense_variant	3/3	1	NM_018053.4	ENSP00000362991.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

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

Jun 16, 2024

The c.593G>A (p.G198D) alteration is located in exon 3 (coding exon 3) of the XKR8 gene. This alteration results from a G to A substitution at nucleotide position 593, causing the glycine (G) at amino acid position 198 to be replaced by an aspartic acid (D). 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	0.18
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.20
Sift	Benign	0.29	T
Sift4G	Benign	0.33	T
Polyphen		0.55	P
Vest4		0.19
MutPred		0.43		Gain of solvent accessibility (P = 0.1583);
MVP		0.41
MPC		0.62
ClinPred		0.14	T
GERP RS		0.37
Varity_R		0.38
gMVP		0.47

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

LitVar

Other links and lift over

dbSNP: rs1638575673; hg19: chr1-28293116;