Variant chrX-46472758-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001129898.2(KRBOX4):c.262C>G(p.Gln88Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000755 in 1,205,698 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 31 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000081 ( 0 hom. 31 hem. )

Consequence

KRBOX4
NM_001129898.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.66

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.039812654).

BS2

High Hemizygotes in GnomAdExome4 at 31 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRBOX4	NM_001129898.2 link	c.262C>G	p.Gln88Glu	missense_variant	6/6	ENST00000344302.9	NP_001123370.1	Q5JUW0-1
KRBOX4	NM_017776.3 link	c.247C>G	p.Gln83Glu	missense_variant	6/6		NP_060246.2	Q5JUW0-2
KRBOX4	NM_001129899.2 link	c.*9C>G		3_prime_UTR_variant	7/7		NP_001123371.1	Q5JUW0-3
KRBOX4	NM_001129900.2 link	c.*9C>G		3_prime_UTR_variant	7/7		NP_001123372.1	Q5JUW0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KRBOX4	ENST00000344302.9 link	c.262C>G	p.Gln88Glu	missense_variant	6/6	2	NM_001129898.2	ENSP00000345797.4	Q5JUW0-1
KRBOX4	ENST00000487081.1 link	c.*6C>G		3_prime_UTR_variant	6/6	1		ENSP00000418076.1	Q5JUW0-3
KRBOX4	ENST00000298190.10 link	c.247C>G	p.Gln83Glu	missense_variant	6/6	2		ENSP00000298190.6	Q5JUW0-2
KRBOX4	ENST00000478600.5 link	c.238+9465C>G		intron_variant		2		ENSP00000418146.1	C9J950

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

111301

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33509

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:

0.000566

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

GnomAD3 exomes

AF:

0.0000393

AC:

AN:

178251

Hom.:

AF XY:

0.0000631

AC XY:

AN XY:

63431

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000511

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000813

AC:

AN:

1094397

Hom.:

Cov.:

AF XY:

0.0000860

AC XY:

AN XY:

360313

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00292

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000180

AC:

AN:

111301

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33509

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000566

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 22, 2024

The c.262C>G (p.Q88E) alteration is located in exon 6 (coding exon 4) of the KRBOX4 gene. This alteration results from a C to G substitution at nucleotide position 262, causing the glutamine (Q) at amino acid position 88 to be replaced by a glutamic acid (E). 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

0.077

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.88

CADD

Benign

6.7

DANN

Benign

0.97

DEOGEN2

Benign

0.013

T;.

FATHMM_MKL

Benign

0.063

LIST_S2

Benign

0.012

T;T

M_CAP

Benign

0.0039

MetaRNN

Benign

0.040

T;T

MetaSVM

Benign

-0.76

MutationAssessor

Benign

0.47

N;.

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.037

Sift

Benign

0.22

T;T

Sift4G

Benign

0.47

T;T

Polyphen

0.0010

B;B

Vest4

0.12

MutPred

0.34

Gain of loop (P = 0.0166);.;

MVP

0.58

MPC

0.48

ClinPred

0.048

GERP RS

1.5

Varity_R

0.24

gMVP

0.035

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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