8-55102718-C-T

Variant names:

• chr8-55102718-C-T
• rs984826220
• NM_052898.2:c.230C>T

Variant summary

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

The NM_052898.2(XKR4):​c.230C>T​(p.Ser77Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000121 in 1,152,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000034 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: XKR4 NM_052898.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.39

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13445798).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XKR4	NM_052898.2	c.230C>T	p.Ser77Leu	missense_variant	Exon 1 of 3	ENST00000327381.7	NP_443130.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XKR4	ENST00000327381.7	c.230C>T	p.Ser77Leu	missense_variant	Exon 1 of 3	1	NM_052898.2	ENSP00000328326.5

Frequencies

GnomAD3 genomes AF: 0.0000341 AC: 5 AN: 146580 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000985

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000677

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000895 AC: 9 AN: 1005716 Hom.: 0 Cov.: 30 AF XY: 0.00000843 AC XY: 4 AN XY: 474286

Gnomad4 AFR exome AF: 0.000350

Gnomad4 AMR exome AF: 0.00

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: 0.00000115

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000341 AC: 5 AN: 146580 Hom.: 0 Cov.: 31 AF XY: 0.0000421 AC XY: 3 AN XY: 71322

Gnomad4 AFR AF: 0.0000985

Gnomad4 AMR AF: 0.0000677

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 09, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.230C>T (p.S77L) alteration is located in exon 1 (coding exon 1) of the XKR4 gene. This alteration results from a C to T substitution at nucleotide position 230, causing the serine (S) at amino acid position 77 to be replaced by a leucine (L). 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	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.025	T;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.52	.;T
M_CAP	Pathogenic	0.76	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.59	N;.
REVEL	Benign	0.28
Sift	Benign	0.26	T;.
Sift4G	Uncertain	0.045	D;D
Polyphen		0.0040	B;B
Vest4		0.15
MutPred		0.26		Loss of glycosylation at S77 (P = 0.0027);Loss of glycosylation at S77 (P = 0.0027);
MVP		0.082
MPC		0.57
ClinPred		0.13	T
GERP RS		3.5
Varity_R		0.064
gMVP		0.10

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: rs984826220; hg19: chr8-56015278;