1-27960260-G-C

Position:

• chr1-27960260-G-C

Variant summary

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

The NM_018053.4(XKR8):​c.191G>C​(p.Ser64Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000073 in 1,369,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: XKR8 NM_018053.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.13

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XKR8	NM_018053.4	c.191G>C	p.Ser64Thr	missense_variant	1/3	ENST00000373884.6	NP_060523.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XKR8	ENST00000373884.6	c.191G>C	p.Ser64Thr	missense_variant	1/3	1	NM_018053.4	ENSP00000362991	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.30e-7 AC: 1 AN: 1369150 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 675044

Gnomad4 AFR exome AF: 0.00

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: 9.32e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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 15, 2024

The c.191G>C (p.S64T) alteration is located in exon 1 (coding exon 1) of the XKR8 gene. This alteration results from a G to C substitution at nucleotide position 191, causing the serine (S) at amino acid position 64 to be replaced by a threonine (T). 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	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.60	T
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.090	D
MutationAssessor	Pathogenic	3.5	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.66
Sift	Uncertain	0.014	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.50
MutPred		0.92		Gain of helix (P = 0.2294);
MVP		0.65
MPC		0.95
ClinPred		0.99	D
GERP RS		3.7
Varity_R		0.74
gMVP		0.85

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: chr1-28286771;