Variant X-46472847-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001129898.2(KRBOX4):c.351T>A(p.Asp117Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000826 in 1,210,185 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 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 0.000027 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.0000064 ( 0 hom. 3 hem. )

Consequence

KRBOX4
NM_001129898.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.822

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07964036).

BS2

High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRBOX4	NM_001129898.2 linkuse as main transcript	c.351T>A	p.Asp117Glu	missense_variant	6/6	ENST00000344302.9	NP_001123370.1	Q5JUW0-1
KRBOX4	NM_017776.3 linkuse as main transcript	c.336T>A	p.Asp112Glu	missense_variant	6/6		NP_060246.2	Q5JUW0-2
KRBOX4	NM_001129899.2 linkuse as main transcript	c.*98T>A		3_prime_UTR_variant	7/7		NP_001123371.1	Q5JUW0-3
KRBOX4	NM_001129900.2 linkuse as main transcript	c.*98T>A		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 linkuse as main transcript	c.351T>A	p.Asp117Glu	missense_variant	6/6	2	NM_001129898.2	ENSP00000345797.4	Q5JUW0-1
KRBOX4	ENST00000487081.1 linkuse as main transcript	c.*95T>A		3_prime_UTR_variant	6/6	1		ENSP00000418076.1	Q5JUW0-3
KRBOX4	ENST00000298190.10 linkuse as main transcript	c.336T>A	p.Asp112Glu	missense_variant	6/6	2		ENSP00000298190.6	Q5JUW0-2
KRBOX4	ENST00000478600.5 linkuse as main transcript	c.238+9554T>A		intron_variant		2		ENSP00000418146.1	C9J950

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

111999

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34157

show subpopulations

Gnomad AFR

AF:

0.0000974

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000109

AC:

AN:

183290

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67802

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

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:

0.00000637

AC:

AN:

1098186

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

363546

show subpopulations

Gnomad4 AFR exome

AF:

0.000265

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000268

AC:

AN:

111999

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34157

show subpopulations

Gnomad4 AFR

AF:

0.0000974

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

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

May 24, 2023

The c.351T>A (p.D117E) alteration is located in exon 6 (coding exon 4) of the KRBOX4 gene. This alteration results from a T to A substitution at nucleotide position 351, causing the aspartic acid (D) at amino acid position 117 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

0.16

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.79

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.0037

T;.

FATHMM_MKL

Benign

0.083

LIST_S2

Benign

0.36

T;T

M_CAP

Benign

0.0020

MetaRNN

Benign

0.080

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.085

N;.

PrimateAI

Benign

0.32

PROVEAN

Benign

0.040

N;N

REVEL

Benign

0.046

Sift

Benign

0.82

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.98

D;D

Vest4

0.17

MutPred

0.30

Gain of disorder (P = 0.129);.;

MVP

0.48

MPC

1.3

ClinPred

0.11

GERP RS

-0.21

Varity_R

0.081

gMVP

0.011

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