NM_001101362.3:c.15dupA

Variant names:

• chr15-65076829-C-CA
• rs1555407522
• NM_001101362.3:c.15dupA

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001101362.3(KBTBD13):​c.15dupA​(p.Gln6ThrfsTer139) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KBTBD13 NM_001101362.3 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.95

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]

RASL12 (HGNC:30289): (RAS like family 12) Predicted to enable GDP binding activity; GTP binding activity; and GTPase activity. Predicted to be involved in signal transduction. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KBTBD13	NM_001101362.3	c.15dupA	p.Gln6ThrfsTer139	frameshift_variant	Exon 1 of 1	ENST00000432196.5	NP_001094832.1
RASL12	NM_001379429.1	c.-232dupT		upstream_gene_variant			NP_001366358.1
RASL12	XM_011521660.4	c.-281dupT		upstream_gene_variant			XP_011519962.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KBTBD13	ENST00000432196.5	c.15dupA	p.Gln6ThrfsTer139	frameshift_variant	Exon 1 of 1	6	NM_001101362.3	ENSP00000388723.2
RASL12	ENST00000434605.2	c.-232dupT		upstream_gene_variant		2		ENSP00000412787.2

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

not provided Uncertain:1

Jan 08, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.15dupA variant in the KBTBD13 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.15dupA variant causes a frameshift starting with codon Glutamine 6, changes this amino acid to a Threonine residue, and creates a premature Stop codon at position 139 of the new reading frame, denoted p.Gln6ThrfsX139. This variant is predicted to cause loss of normal protein function through protein truncation, however, loss-of-function is not an established mechanism of disease for the KBTBD13 gene. The c.15dupA variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.15dupA as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

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: rs1555407522; hg19: chr15-65369167;