1-27966695-A-C

Position:

• chr1-27966695-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018053.4(XKR8):​c.683A>C​(p.Tyr228Ser) 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. 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: XKR8 NM_018053.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0140

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28234887).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XKR8	NM_018053.4	c.683A>C	p.Tyr228Ser	missense_variant	3/3	ENST00000373884.6	NP_060523.2
XKR8	XM_011541679.4	c.845A>C	p.Tyr282Ser	missense_variant	5/5		XP_011539981.1
XKR8	XM_011541680.4	c.737A>C	p.Tyr246Ser	missense_variant	4/4		XP_011539982.1
XKR8	XM_047423826.1	c.*79A>C		3_prime_UTR_variant	4/4		XP_047279782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XKR8	ENST00000373884.6	c.683A>C	p.Tyr228Ser	missense_variant	3/3	1	NM_018053.4	ENSP00000362991	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

Oct 05, 2023

The c.683A>C (p.Y228S) alteration is located in exon 3 (coding exon 3) of the XKR8 gene. This alteration results from a A to C substitution at nucleotide position 683, causing the tyrosine (Y) at amino acid position 228 to be replaced by a serine (S). 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	0.10
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	14
DANN	Benign	0.87
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Benign	0.21
Sift	Benign	0.13	T
Sift4G	Benign	0.17	T
Polyphen		0.32	B
Vest4		0.22
MutPred		0.72		Gain of glycosylation at Y228 (P = 0.0322);
MVP		0.19
MPC		0.71
ClinPred		0.81	D
GERP RS		-0.39
Varity_R		0.40
gMVP		0.71

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: chr1-28293206;