chr8-55523706-T-C

Position:

• chr8-55523706-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_052898.2(XKR4):​c.1432T>C​(p.Tyr478His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 4.87

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.841

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XKR4	NM_052898.2	c.1432T>C	p.Tyr478His	missense_variant	3/3	ENST00000327381.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XKR4	ENST00000327381.7	c.1432T>C	p.Tyr478His	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

May 26, 2024

The c.1432T>C (p.Y478H) alteration is located in exon 3 (coding exon 3) of the XKR4 gene. This alteration results from a T to C substitution at nucleotide position 1432, causing the tyrosine (Y) at amino acid position 478 to be replaced by a histidine (H). 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	0.17
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.092	T;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	.;D
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.1	N;.
REVEL	Uncertain	0.34
Sift	Benign	0.11	T;.
Sift4G	Benign	0.13	T;T
Polyphen		0.98	D;D
Vest4		0.79
MutPred		0.76		Gain of methylation at K479 (P = 0.0464);Gain of methylation at K479 (P = 0.0464);
MVP		0.35
MPC		1.7
ClinPred		0.89	D
GERP RS		5.7
Varity_R		0.17
gMVP		0.78

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: chr8-56436265;