rs767384093

chr15-65077105-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_Strong BS2

The NM_001101362.3(KBTBD13):c.290T>C(p.Leu97Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000505 in 1,523,372 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L97L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: KBTBD13 NM_001101362.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:1
• Conservation: PhyloP100: 4.80

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 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• BS2: High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KBTBD13	NM_001101362.3	c.290T>C	p.Leu97Pro	missense_variant	1/1	ENST00000432196.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KBTBD13	ENST00000432196.5	c.290T>C	p.Leu97Pro	missense_variant	1/1		NM_001101362.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 151954 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000742 AC: 9 AN: 121256 Hom.: 0 AF XY: 0.0000746 AC XY: 5 AN XY: 66992

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000259

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: 0.0000662

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000496 AC: 68 AN: 1371308 Hom.: 0 Cov.: 58 AF XY: 0.0000532 AC XY: 36 AN XY: 676950

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000290

Gnomad4 ASJ exome AF: 0.0000407

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000643

Gnomad4 FIN exome AF: 0.0000277

Gnomad4 NFE exome AF: 0.0000439

Gnomad4 OTH exome AF: 0.0000526

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152064 Hom.: 0 Cov.: 34 AF XY: 0.0000403 AC XY: 3 AN XY: 74382

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000442

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000127 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nemaline myopathy 6 Pathogenic:1 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 25, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 17, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	NeuroMeGen, Hospital Clinico Santiago de Compostela	Oct 08, 2018	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 09, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.25
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.44	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	0.99	D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.78		Gain of disorder (P = 0.0494);
MVP		0.69
MPC		1.9
ClinPred		0.47	T
GERP RS		4.4
Varity_R		0.96
gMVP		0.96

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

Other links and lift over

dbSNP: rs767384093; hg19: chr15-65369443;