chrX-46463282-G-A

Position:

chrX-46463282-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001129898.2(KRBOX4):c.227G>A(p.Arg76Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000207 in 1,210,408 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000020 ( 0 hom. 8 hem. )

Consequence

KRBOX4
NM_001129898.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -1.03

Variant links:

Genes affected

KRBOX4 (HGNC:26007): (KRAB box domain containing 4) This encodes a zinc finger protein with an N-terminal KRAB (Kruppel-associated) domain found in transcriptional repressors. This gene is located in a region of the X chromosome thought to be involved in nonsyndromic X-linked cognitive disability. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

KRBOX4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.053731114).

BP6

Variant X-46463282-G-A is Benign according to our data. Variant chrX-46463282-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2660378.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Hemizygotes in GnomAdExome4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRBOX4	NM_001129898.2 link	c.227G>A	p.Arg76Gln	missense_variant	5/6	ENST00000344302.9	NP_001123370.1	Q5JUW0-1
KRBOX4	NM_017776.3 link	c.227G>A	p.Arg76Gln	missense_variant	5/6		NP_060246.2	Q5JUW0-2
KRBOX4	NM_001129899.2 link	c.227G>A	p.Arg76Gln	missense_variant	5/7		NP_001123371.1	Q5JUW0-3
KRBOX4	NM_001129900.2 link	c.227G>A	p.Arg76Gln	missense_variant	5/7		NP_001123372.1	Q5JUW0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRBOX4	ENST00000344302.9 link	c.227G>A	p.Arg76Gln	missense_variant	5/6	2	NM_001129898.2	ENSP00000345797.4		Q5JUW0-1

Frequencies

GnomAD3 genomes

AF:

0.0000267

AC:

AN:

112361

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34525

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:

0.0000564

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000491

AC:

AN:

183341

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

67809

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.000134

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000855

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000200

AC:

AN:

1098047

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

363403

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000166

Gnomad4 OTH exome

AF:

0.000108

GnomAD4 genome

AF:

0.0000267

AC:

AN:

112361

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34525

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000564

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000254

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2024

The c.227G>A (p.R76Q) alteration is located in exon 5 (coding exon 3) of the KRBOX4 gene. This alteration results from a G to A substitution at nucleotide position 227, causing the arginine (R) at amino acid position 76 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

KRBOX4: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.99

CADD

Benign

0.088

DANN

Benign

0.28

DEOGEN2

Benign

0.0057

T;.;.;.;.;.

FATHMM_MKL

Benign

0.0067

LIST_S2

Benign

0.041

T;T;.;T;T;T

M_CAP

Benign

0.00082

MetaRNN

Benign

0.054

T;T;T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.46

N;N;N;.;.;N

PrimateAI

Benign

0.19

PROVEAN

Benign

0.59

N;N;N;N;N;N

REVEL

Benign

0.034

Sift

Benign

0.59

T;T;T;T;T;T

Sift4G

Benign

0.61

T;T;T;T;T;T

Polyphen

0.0050

B;B;B;B;.;B

Vest4

0.079

MVP

0.33

MPC

0.51

ClinPred

0.11

GERP RS

-6.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.028

gMVP

0.039

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over