8-55103192-G-C

Position:

• chr8-55103192-G-C

Variant summary

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

The NM_052898.2(XKR4):​c.704G>C​(p.Gly235Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: XKR4 NM_052898.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.27

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=0.07313281).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XKR4	NM_052898.2	c.704G>C	p.Gly235Ala	missense_variant	1/3	ENST00000327381.7	NP_443130.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XKR4	ENST00000327381.7	c.704G>C	p.Gly235Ala	missense_variant	1/3	1	NM_052898.2	ENSP00000328326	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461720 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727172

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Nov 18, 2023

The c.704G>C (p.G235A) alteration is located in exon 1 (coding exon 1) of the XKR4 gene. This alteration results from a G to C substitution at nucleotide position 704, causing the glycine (G) at amino acid position 235 to be replaced by an alanine (A). 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	0.069
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Benign	0.78
DEOGEN2	Benign	0.023	T;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.50	.;T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.073	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.60	N;N
MutationTaster	Benign	0.96	N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.34	N;.
REVEL	Benign	0.15
Sift	Benign	0.78	T;.
Sift4G	Benign	0.44	T;T
Polyphen		0.0010	B;B
Vest4		0.20
MutPred		0.43		Gain of helix (P = 0.062);Gain of helix (P = 0.062);
MVP		0.068
MPC		0.69
ClinPred		0.041	T
GERP RS		3.0
Varity_R		0.080
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr8-56015752;