chr8-70733976-T-A

Position:

• chr8-70733976-T-A

Variant summary

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

The NM_001011720.2(XKR9):​c.674T>A​(p.Phe225Tyr) 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. 14/21 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: XKR9 NM_001011720.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.11

Genes affected

XKR9 (HGNC:20937): (XK related 9) Predicted to enable phospholipid scramblase activity. Predicted to be involved in apoptotic process involved in development; engulfment of apoptotic cell; and 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32200974).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XKR9	NM_001011720.2	c.674T>A	p.Phe225Tyr	missense_variant	5/5	ENST00000408926.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XKR9	ENST00000408926.8	c.674T>A	p.Phe225Tyr	missense_variant	5/5	1	NM_001011720.2	P1
XKR9	ENST00000520030.5	c.674T>A	p.Phe225Tyr	missense_variant	6/6	1		P1
XKR9	ENST00000520092.5	c.*414T>A		3_prime_UTR_variant, NMD_transcript_variant	6/6	2
XKR9	ENST00000520273.1	n.352+26823T>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Mar 21, 2023

The c.674T>A (p.F225Y) alteration is located in exon 5 (coding exon 3) of the XKR9 gene. This alteration results from a T to A substitution at nucleotide position 674, causing the phenylalanine (F) at amino acid position 225 to be replaced by a tyrosine (Y). 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	0.16
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0052	T;T
Eigen	Benign	-0.0065
Eigen_PC	Benign	-0.0071
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.50	.;T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.84	N;N
REVEL	Benign	0.22
Sift	Benign	0.035	D;D
Sift4G	Uncertain	0.057	T;T
Polyphen		0.95	P;P
Vest4		0.33
MutPred		0.64		Loss of stability (P = 0.0932);Loss of stability (P = 0.0932);
MVP		0.46
MPC		0.0037
ClinPred		0.92	D
GERP RS		4.7
Varity_R		0.27
gMVP		0.21

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: chr8-71646211;