Variant 3-67003668-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_032505.3(KBTBD8):c.701A>C(p.Glu234Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,852 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: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KBTBD8
NM_032505.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.43

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:

KBTBD8 (HGNC:):

KBTBD8 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.771

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KBTBD8	NM_032505.3 linkuse as main transcript	c.701A>C	p.Glu234Ala	missense_variant	3/4	ENST00000417314.2	NP_115894.2	Q8NFY9-1
KBTBD8	XM_005264771.4 linkuse as main transcript	c.470A>C	p.Glu157Ala	missense_variant	2/3		XP_005264828.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KBTBD8	ENST00000417314.2 linkuse as main transcript	c.701A>C	p.Glu234Ala	missense_variant	3/4	2	NM_032505.3	ENSP00000401878.2	Q8NFY9-1
KBTBD8	ENST00000484414.5 linkuse as main transcript	c.470A>C	p.Glu157Ala	missense_variant	2/2	3		ENSP00000417341.1	C9J331
KBTBD8	ENST00000460576.5 linkuse as main transcript	c.17-4254A>C		intron_variant		2		ENSP00000419738.1	Q8NFY9-2
KBTBD8	ENST00000469661.1 linkuse as main transcript	n.407A>C		non_coding_transcript_exon_variant	3/3	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727236

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

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

Feb 21, 2024

The c.701A>C (p.E234A) alteration is located in exon 3 (coding exon 3) of the KBTBD8 gene. This alteration results from a A to C substitution at nucleotide position 701, causing the glutamic acid (E) at amino acid position 234 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

0.12

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

T;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.064

MetaRNN

Pathogenic

0.77

D;D

MetaSVM

Benign

-0.33

MutationAssessor

Benign

1.9

.;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.6

D;D

REVEL

Uncertain

0.63

Sift

Benign

0.044

D;D

Sift4G

Benign

0.29

T;D

Polyphen

0.93

.;P

Vest4

0.76

MutPred

0.57

.;Gain of ubiquitination at K238 (P = 0.0773);

MVP

0.85

MPC

0.31

ClinPred

0.97

GERP RS

4.9

Varity_R

0.37

gMVP

0.51

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