8-70706933-G-C

Variant names:

• chr8-70706933-G-C
• rs140607007
• NM_001011720.2:c.273G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001011720.2(XKR9):​c.273G>C​(p.Arg91Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,455,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: XKR9 NM_001011720.2 missense, splice_region
• Scores: Splicing: ADA: 0.7425
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.57
• Publications: 0 publications found

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]

ENSG00000285579 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001011720.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XKR9	NM_001011720.2	MANE Select	c.273G>C	p.Arg91Ser	missense splice_region	Exon 4 of 5	NP_001011720.1	Q5GH70
	XKR9	NM_001287259.2		c.273G>C	p.Arg91Ser	missense splice_region	Exon 5 of 6	NP_001274188.1	Q5GH70
	XKR9	NM_001287260.2		c.273G>C	p.Arg91Ser	missense splice_region	Exon 4 of 5	NP_001274189.1	Q5GH70

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XKR9	ENST00000408926.8	TSL:1 MANE Select	c.273G>C	p.Arg91Ser	missense splice_region	Exon 4 of 5	ENSP00000386141.3	Q5GH70
	XKR9	ENST00000520030.5	TSL:1	c.273G>C	p.Arg91Ser	missense splice_region	Exon 5 of 6	ENSP00000431088.1	Q5GH70
	XKR9	ENST00000920915.1		c.273G>C	p.Arg91Ser	missense splice_region	Exon 4 of 5	ENSP00000590974.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000117 AC: 17 AN: 1455280 Hom.: 0 Cov.: 30 AF XY: 0.00000552 AC XY: 4 AN XY: 724234

African (AFR) AF: 0.00 AC: 0 AN: 33304

American (AMR) AF: 0.00 AC: 0 AN: 44420

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25972

East Asian (EAS) AF: 0.00 AC: 0 AN: 39578

South Asian (SAS) AF: 0.00 AC: 0 AN: 85782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.0000145 AC: 16 AN: 1107170

Other (OTH) AF: 0.0000166 AC: 1 AN: 60146

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.094	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		2.6
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.94		Loss of MoRF binding (P = 0.0159)
MVP		0.89
MPC		0.0063
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.97
gMVP		0.86
Mutation Taster		=9/91	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.74
dbscSNV1_RF	Benign	0.70
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

Other links and lift over

dbSNP: rs140607007; hg19: chr8-71619168;