Genetic Variant NM_052898.2:c.230C>T (chr8-55102718-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_052898.2(XKR4):c.230C>T(p.Ser77Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000121 in 1,152,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S77A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000034 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

XKR4
NM_052898.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.39

Publications

0 publications found

Variant links:

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]

XKR4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13445798).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052898.2. 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
	XKR4	NM_052898.2	MANE Select	c.230C>T	p.Ser77Leu	missense	Exon 1 of 3	NP_443130.1	Q5GH76

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XKR4	ENST00000327381.7	TSL:1 MANE Select	c.230C>T	p.Ser77Leu	missense	Exon 1 of 3	ENSP00000328326.5	Q5GH76

Frequencies

GnomAD3 genomes

AF:

0.0000341

AC:

AN:

146580

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000985

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000677

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000895

AC:

AN:

1005716

Hom.:

Cov.:

AF XY:

0.00000843

AC XY:

AN XY:

474286

show subpopulations

African (AFR)

AF:

0.000350

AC:

AN:

20020

American (AMR)

AF:

0.00

AC:

AN:

5796

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10756

East Asian (EAS)

AF:

0.00

AC:

AN:

19066

South Asian (SAS)

AF:

0.00

AC:

AN:

18894

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20002

Middle Eastern (MID)

AF:

0.000399

AC:

AN:

2506

European-Non Finnish (NFE)

AF:

0.00000115

AC:

AN:

870784

Other (OTH)

AF:

0.00

AC:

AN:

37892

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000341

AC:

AN:

146580

Hom.:

Cov.:

AF XY:

0.0000421

AC XY:

AN XY:

71322

show subpopulations

African (AFR)

AF:

0.0000985

AC:

AN:

40592

American (AMR)

AF:

0.0000677

AC:

AN:

14768

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3402

East Asian (EAS)

AF:

0.00

AC:

AN:

4982

South Asian (SAS)

AF:

0.00

AC:

AN:

4742

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8918

Middle Eastern (MID)

AF:

0.00

AC:

AN:

302

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65966

Other (OTH)

AF:

0.00

AC:

AN:

2008

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.565

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.025

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.52

M_CAP

Pathogenic

0.76

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.0

PhyloP100

1.4

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.59

REVEL

Benign

0.28

Sift

Benign

0.26

Sift4G

Uncertain

0.045

Polyphen

0.0040

Vest4

0.15

MutPred

0.26

Loss of glycosylation at S77 (P = 0.0027)

MVP

0.082

MPC

0.57

ClinPred

0.13

GERP RS

3.5

PromoterAI

0.074

Neutral

(source)

Varity_R

0.064

gMVP

0.10

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over