chr15-65076849-T-G

Position:

• chr15-65076849-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001101362.3(KBTBD13):​c.34T>G​(p.Trp12Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KBTBD13 NM_001101362.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.437

Genes affected

KBTBD13 (HGNC:37227): (kelch repeat and BTB domain containing 13) The gene belongs to a family of genes encoding proteins containing a BTB domain and several kelch repeats. The BTB domain functions as a protein-protein interaction module, which includes an ability to self-associate or to interact with non-BTB domain-containing proteins. The kelch motif typically occurs in groups of five to seven repeats, and has been found in proteins with diverse functions. Known functions of these family members include transcription regulation, ion channel tetramerization and gating, protein ubiquitination or degradation, and cytoskeleton regulation. The exact function of this family member has yet to be determined. [provided by RefSeq, Jun 2010]

ACMG classification

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=0.2679326).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KBTBD13	NM_001101362.3	c.34T>G	p.Trp12Gly	missense_variant	1/1	ENST00000432196.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KBTBD13	ENST00000432196.5	c.34T>G	p.Trp12Gly	missense_variant	1/1		NM_001101362.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 6 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 24, 2023

This sequence change replaces tryptophan, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 12 of the KBTBD13 protein (p.Trp12Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KBTBD13-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KBTBD13 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Benign	0.89
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	0.89	N
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.29
Sift	Benign	0.24	T
Sift4G	Benign	0.22	T
Polyphen		0.35	B
Vest4		0.40
MutPred		0.71		Gain of disorder (P = 0.0189);
MVP		0.54
MPC		1.0
ClinPred		0.24	T
GERP RS		4.4
Varity_R		0.28
gMVP		0.61

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.

Other links and lift over

hg19: chr15-65369187;