X-46472872-T-G

Position:

chrX-46472872-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001129898.2(KRBOX4):c.376T>G(p.Cys126Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000895 in 111,784 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Failed GnomAD Quality Control

Consequence

KRBOX4
NM_001129898.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.951

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28674203).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRBOX4	NM_001129898.2 linkuse as main transcript	c.376T>G	p.Cys126Gly	missense_variant	6/6	ENST00000344302.9	NP_001123370.1	Q5JUW0-1
KRBOX4	NM_017776.3 linkuse as main transcript	c.361T>G	p.Cys121Gly	missense_variant	6/6		NP_060246.2	Q5JUW0-2
KRBOX4	NM_001129899.2 linkuse as main transcript	c.*123T>G		3_prime_UTR_variant	7/7		NP_001123371.1	Q5JUW0-3
KRBOX4	NM_001129900.2 linkuse as main transcript	c.*123T>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 linkuse as main transcript	c.376T>G	p.Cys126Gly	missense_variant	6/6	2	NM_001129898.2	ENSP00000345797.4	Q5JUW0-1
KRBOX4	ENST00000487081.1 linkuse as main transcript	c.*120T>G		3_prime_UTR_variant	6/6	1		ENSP00000418076.1	Q5JUW0-3
KRBOX4	ENST00000298190.10 linkuse as main transcript	c.361T>G	p.Cys121Gly	missense_variant	6/6	2		ENSP00000298190.6	Q5JUW0-2
KRBOX4	ENST00000478600.5 linkuse as main transcript	c.238+9579T>G		intron_variant		2		ENSP00000418146.1	C9J950

Frequencies

GnomAD3 genomes

AF:

0.00000895

AC:

AN:

111784

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33962

show subpopulations

Gnomad AFR

AF:

0.0000326

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:

0.00000546

AC:

AN:

183263

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67779

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

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

Data not reliable, filtered out with message: AS_VQSR

AF:

9.11e-7

AC:

AN:

1098188

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363546

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000284

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:

0.00000895

AC:

AN:

111784

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33962

show subpopulations

Gnomad4 AFR

AF:

0.0000326

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:

0.0000264

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

Oct 09, 2024

The c.376T>G (p.C126G) alteration is located in exon 6 (coding exon 4) of the KRBOX4 gene. This alteration results from a T to G substitution at nucleotide position 376, causing the cysteine (C) at amino acid position 126 to be replaced by a glycine (G). 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

0.12

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.69

CADD

Benign

5.3

DANN

Benign

0.77

DEOGEN2

Benign

0.12

T;.

FATHMM_MKL

Benign

0.085

LIST_S2

Benign

0.54

T;T

M_CAP

Benign

0.0015

MetaRNN

Benign

0.29

T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.9

L;.

PrimateAI

Benign

0.22

PROVEAN

Uncertain

-2.4

N;D

REVEL

Benign

0.12

Sift

Benign

0.23

T;T

Sift4G

Benign

0.30

T;T

Polyphen

0.66

P;P

Vest4

0.25

MutPred

0.74

Loss of stability (P = 0.0021);.;

MVP

0.092

MPC

0.58

ClinPred

0.12

GERP RS

2.7

Varity_R

0.12

gMVP

0.039

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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