Genetic Variant NM_173683.4:c.85G>C (chr8-11201255-C-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_173683.4(XKR6):c.85G>C(p.Glu29Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000115 in 1,567,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

XKR6
NM_173683.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.934

Publications

0 publications found

Variant links:

Genes affected

XKR6 (HGNC:27806): (XK related 6) 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]

XKR6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13462684).

BS2

High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XKR6	NM_173683.4 link	c.85G>C	p.Glu29Gln	missense_variant	Exon 1 of 3	ENST00000416569.3	NP_775954.2	Q5GH73-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XKR6	ENST00000416569.3 link	c.85G>C	p.Glu29Gln	missense_variant	Exon 1 of 3	1	NM_173683.4	ENSP00000416707.2		Q5GH73-1
XKR6	ENST00000297303.4 link	c.85G>C	p.Glu29Gln	missense_variant	Exon 1 of 2	1		ENSP00000297303.4		Q96KT3

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151270

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000120

AC:

AN:

1416488

Hom.:

Cov.:

AF XY:

0.0000156

AC XY:

AN XY:

703146

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31194

American (AMR)

AF:

0.0000239

AC:

AN:

41766

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25150

East Asian (EAS)

AF:

0.00

AC:

AN:

36858

South Asian (SAS)

AF:

0.00

AC:

AN:

81758

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35816

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5116

European-Non Finnish (NFE)

AF:

0.0000145

AC:

AN:

1100022

Other (OTH)

AF:

0.00

AC:

AN:

58808

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

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:

0.00000661

AC:

AN:

151270

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73868

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41204

American (AMR)

AF:

0.00

AC:

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5106

South Asian (SAS)

AF:

0.00

AC:

AN:

4794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10550

Middle Eastern (MID)

AF:

0.00

AC:

AN:

302

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67628

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 07, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.85G>C (p.E29Q) alteration is located in exon 1 (coding exon 1) of the XKR6 gene. This alteration results from a G to C substitution at nucleotide position 85, causing the glutamic acid (E) at amino acid position 29 to be replaced by a glutamine (Q). 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

0.082

BayesDel_addAF

Benign

-0.0066

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.018

T;T

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.53

T;T

M_CAP

Pathogenic

0.91

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.90

L;.

PhyloP100

0.93

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.14

N;N

REVEL

Benign

0.14

Sift

Benign

0.20

T;T

Sift4G

Benign

0.40

T;T

Polyphen

0.099

B;.

Vest4

0.20

MutPred

0.24

Loss of phosphorylation at S26 (P = 0.2693);Loss of phosphorylation at S26 (P = 0.2693);

MVP

0.17

MPC

1.1

ClinPred

0.12

GERP RS

1.8

PromoterAI

-0.042

Neutral

(source)

Varity_R

0.14

gMVP

0.23

Mutation Taster

=84/16

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over