Variant X-46472957-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001129898.2(KRBOX4):c.461A>C(p.Lys154Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000356 in 112,248 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000019 ( 0 hom. 5 hem. )

Failed GnomAD Quality Control

Consequence

KRBOX4
NM_001129898.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.45

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19614872).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRBOX4	NM_001129898.2 linkuse as main transcript	c.461A>C	p.Lys154Thr	missense_variant	6/6	ENST00000344302.9	NP_001123370.1	Q5JUW0-1
KRBOX4	NM_017776.3 linkuse as main transcript	c.446A>C	p.Lys149Thr	missense_variant	6/6		NP_060246.2	Q5JUW0-2
KRBOX4	NM_001129899.2 linkuse as main transcript	c.*208A>C		3_prime_UTR_variant	7/7		NP_001123371.1	Q5JUW0-3
KRBOX4	NM_001129900.2 linkuse as main transcript	c.*208A>C		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.461A>C	p.Lys154Thr	missense_variant	6/6	2	NM_001129898.2	ENSP00000345797.4	Q5JUW0-1
KRBOX4	ENST00000487081.1 linkuse as main transcript	c.*205A>C		3_prime_UTR_variant	6/6	1		ENSP00000418076.1	Q5JUW0-3
KRBOX4	ENST00000298190.10 linkuse as main transcript	c.446A>C	p.Lys149Thr	missense_variant	6/6	2		ENSP00000298190.6	Q5JUW0-2
KRBOX4	ENST00000478600.5 linkuse as main transcript	c.238+9664A>C		intron_variant		2		ENSP00000418146.1	C9J950

Frequencies

GnomAD3 genomes

AF:

0.0000356

AC:

AN:

112248

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34404

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:

0.0000751

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000110

AC:

AN:

182240

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

66932

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000246

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000191

AC:

AN:

1097990

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

363364

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000238

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000356

AC:

AN:

112248

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34404

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:

0.0000751

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

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

Nov 08, 2022

The c.461A>C (p.K154T) alteration is located in exon 6 (coding exon 4) of the KRBOX4 gene. This alteration results from a A to C substitution at nucleotide position 461, causing the lysine (K) at amino acid position 154 to be replaced by a threonine (T). 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

0.17

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.12

T;.

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.53

T;T

M_CAP

Benign

0.0028

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.5

L;.

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-2.8

D;D

REVEL

Benign

0.066

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.021

D;D

Polyphen

0.99

D;D

Vest4

0.17

MVP

0.49

MPC

0.52

ClinPred

0.34

GERP RS

-0.60

Varity_R

0.22

gMVP

0.11

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