Genetic Variant KBTBD7:p.Arg421Cys (chr13-41192997-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_032138.7(KBTBD7):c.1261C>T(p.Arg421Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

KBTBD7
NM_032138.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.75

Variant links:

Genes affected

KBTBD7 (HGNC:25266): (kelch repeat and BTB domain containing 7) The protein encoded by this gene is a transcriptional activator, having been shown to increase the transcription of activator protein-1 and serum response element. The encoded protein can also form a complex with KBTBD6 and CUL3, which regulates the ubiquitylation and degradation of TIAM1, which is a regulator of RAC1. [provided by RefSeq, Jul 2016]

KBTBD7 links:

ENSG00000278390 (HGNC:56824): (KBTBD6 divergent transcript)

ENSG00000278390 links:

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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=0.18937027).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KBTBD7	NM_032138.7 link	c.1261C>T	p.Arg421Cys	missense_variant	Exon 1 of 1	ENST00000379483.4	NP_115514.2	Q8WVZ9
KBTBD6-DT	NR_120423.1 link	n.350+30594G>A		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KBTBD7	ENST00000379483.4 link	c.1261C>T	p.Arg421Cys	missense_variant	Exon 1 of 1	6	NM_032138.7	ENSP00000368797.3	Q8WVZ9
ENSG00000278390	ENST00000619407.4 link	n.339+30594G>A		intron_variant	Intron 3 of 3	2
ENSG00000278390	ENST00000661006.1 link	n.245+30594G>A		intron_variant	Intron 2 of 2
ENSG00000278390	ENST00000615685.4 link	n.*162G>A		downstream_gene_variant		4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1261C>T (p.R421C) alteration is located in exon 1 (coding exon 1) of the KBTBD7 gene. This alteration results from a C to T substitution at nucleotide position 1261, causing the arginine (R) at amino acid position 421 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

0.47

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.081

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.0070

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.032

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.94

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.39

Sift

Uncertain

0.017

Sift4G

Pathogenic

0.0010

Polyphen

0.010

Vest4

0.26

MutPred

0.72

Gain of catalytic residue at L422 (P = 0.0123);

MVP

0.72

MPC

0.93

ClinPred

0.70

GERP RS

4.2

Varity_R

0.19

gMVP

0.90

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over