Variant 3-42941308-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001205272.2(KRBOX1):c.119A>G(p.Tyr40Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 1,600,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000086 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

KRBOX1
NM_001205272.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.68

Variant links:

Genes affected

KRBOX1 (HGNC:38708): (KRAB box domain containing 1) Predicted to be involved in regulation of transcription, DNA-templated. [provided by Alliance of Genome Resources, Apr 2022]

KRBOX1 links:

ENSG00000290317 (HGNC:):

ENSG00000290317 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.889

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRBOX1	NM_001205272.2 linkuse as main transcript	c.119A>G	p.Tyr40Cys	missense_variant	3/5	ENST00000383748.9	NP_001192201.1	C9JBD0-1A0A024R2N1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KRBOX1	ENST00000383748.9 linkuse as main transcript	c.119A>G	p.Tyr40Cys	missense_variant	3/5	1	NM_001205272.2	ENSP00000373254.5	C9JBD0-1
ENSG00000290317	ENST00000426937.5 linkuse as main transcript	c.119A>G	p.Tyr40Cys	missense_variant	5/7	3		ENSP00000413859.1
ENSG00000273291	ENST00000446977.2 linkuse as main transcript	c.119A>G	p.Tyr40Cys	missense_variant	3/5	4		ENSP00000477043.1	V9GYS6

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

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:

0.0000128

AC:

AN:

234782

Hom.:

AF XY:

0.00

AC XY:

AN XY:

127164

show subpopulations

Gnomad AFR exome

AF:

0.000201

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:

0.00000276

AC:

AN:

1447972

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

719828

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

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:

0.0000855

AC:

AN:

152034

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.000314

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:

0.0000718

ExAC

AF:

0.0000165

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

Aug 13, 2021

The c.119A>G (p.Y40C) alteration is located in exon 3 (coding exon 2) of the KRBOX1 gene. This alteration results from a A to G substitution at nucleotide position 119, causing the tyrosine (Y) at amino acid position 40 to be replaced by a cysteine (C). 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

Uncertain

0.39

BayesDel_addAF

Benign

-0.065

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

.;T;T;T

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.88

D;.;.;D

M_CAP

Benign

0.016

MetaRNN

Pathogenic

0.89

D;D;D;D

MetaSVM

Benign

-0.73

MutationAssessor

Pathogenic

3.3

.;M;M;M

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-8.9

.;D;D;D

REVEL

Benign

0.20

Sift

Uncertain

0.0010

.;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

0.99

.;D;D;D

Vest4

0.65, 0.67

MutPred

0.76

Loss of phosphorylation at Y40 (P = 0.0697);Loss of phosphorylation at Y40 (P = 0.0697);Loss of phosphorylation at Y40 (P = 0.0697);Loss of phosphorylation at Y40 (P = 0.0697);

MVP

0.33

MPC

0.47

ClinPred

0.99

GERP RS

4.8

Varity_R

0.39

gMVP

0.16

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