Variant 3-66998365-T-G 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_032505.3(KBTBD8):c.10T>G(p.Ser4Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000367 in 1,280,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

KBTBD8
NM_032505.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.42

Variant links:

Genes affected

KBTBD8 (HGNC:30691): (kelch repeat and BTB domain containing 8) Involved in neural crest cell development; neural crest formation; and protein monoubiquitination. Part of Cul3-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

KBTBD8 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=0.14158064).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KBTBD8	NM_032505.3 linkuse as main transcript	c.10T>G	p.Ser4Ala	missense_variant	1/4	ENST00000417314.2	NP_115894.2
KBTBD8	XM_005264771.4 linkuse as main transcript	c.-11T>G		5_prime_UTR_variant	1/3		XP_005264828.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KBTBD8	ENST00000417314.2 linkuse as main transcript	c.10T>G	p.Ser4Ala	missense_variant	1/4	2	NM_032505.3	ENSP00000401878	P1	Q8NFY9-1
KBTBD8	ENST00000460576.5 linkuse as main transcript	c.10T>G	p.Ser4Ala	missense_variant	1/2	2		ENSP00000419738		Q8NFY9-2
KBTBD8	ENST00000484414.5 linkuse as main transcript	c.-11T>G		5_prime_UTR_variant	1/2	3		ENSP00000417341
KBTBD8	ENST00000469661.1 linkuse as main transcript	n.59T>G		non_coding_transcript_exon_variant	1/3	5

Frequencies

GnomAD3 genomes

AF:

0.000141

AC:

AN:

148642

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000445

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000133

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:

0.000492

GnomAD4 exome

AF:

0.0000230

AC:

AN:

1132026

Hom.:

Cov.:

AF XY:

0.0000222

AC XY:

AN XY:

540114

show subpopulations

Gnomad4 AFR exome

AF:

0.00104

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:

0.00000213

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000141

AC:

AN:

148752

Hom.:

Cov.:

AF XY:

0.000138

AC XY:

AN XY:

72580

show subpopulations

Gnomad4 AFR

AF:

0.000444

Gnomad4 AMR

AF:

0.000133

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:

0.000487

Alfa

AF:

0.0000709

Hom.:

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 30, 2022

The c.10T>G (p.S4A) alteration is located in exon 1 (coding exon 1) of the KBTBD8 gene. This alteration results from a T to G substitution at nucleotide position 10, causing the serine (S) at amino acid position 4 to be replaced by an alanine (A). 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

0.054

BayesDel_addAF

Benign

-0.013

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.018

.;T

Eigen

Benign

-0.19

Eigen_PC

Benign

0.0061

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.24

T;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.81

L;L

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.040

N;N

REVEL

Benign

0.068

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

.;D

Polyphen

0.0030

.;B

Vest4

0.34

MVP

0.74

MPC

0.21

ClinPred

0.53

GERP RS

4.2

Varity_R

0.093

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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