rs201466173

chr15-65077176-G-Achr15-65077176-G-Cchr15-65077176-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001101362.3(KBTBD13):c.361G>A(p.Val121Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 1,504,322 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V121L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0039 (19 hom.)
• Consequence: KBTBD13 NM_001101362.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.43

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0073600113).
• BP6: Variant 15-65077176-G-A is Benign according to our data. Variant chr15-65077176-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 316740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-65077176-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00218 (331/152078) while in subpopulation NFE AF= 0.00402 (273/67950). AF 95% confidence interval is 0.00363. There are 0 homozygotes in gnomad4. There are 135 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 332 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KBTBD13	NM_001101362.3	c.361G>A	p.Val121Met	missense_variant	1/1	ENST00000432196.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KBTBD13	ENST00000432196.5	c.361G>A	p.Val121Met	missense_variant	1/1		NM_001101362.3	P1

Frequencies

GnomAD3 genomes AF: 0.00218 AC: 332 AN: 151968 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000797

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.000918

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000284

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00402

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00189 AC: 200 AN: 105916 Hom.: 0 AF XY: 0.00183 AC XY: 108 AN XY: 58934

Gnomad AFR exome AF: 0.000403

Gnomad AMR exome AF: 0.000633

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000896

Gnomad FIN exome AF: 0.000188

Gnomad NFE exome AF: 0.00411

Gnomad OTH exome AF: 0.000924

GnomAD4 exome AF: 0.00388 AC: 5249 AN: 1352244 Hom.: 19 Cov.: 56 AF XY: 0.00385 AC XY: 2565 AN XY: 666232

Gnomad4 AFR exome AF: 0.000428

Gnomad4 AMR exome AF: 0.000932

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.00120

Gnomad4 FIN exome AF: 0.000208

Gnomad4 NFE exome AF: 0.00465

Gnomad4 OTH exome AF: 0.00265

GnomAD4 genome AF: 0.00218 AC: 331 AN: 152078 Hom.: 0 Cov.: 34 AF XY: 0.00182 AC XY: 135 AN XY: 74366

Gnomad4 AFR AF: 0.000795

Gnomad4 AMR AF: 0.000917

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000284

Gnomad4 NFE AF: 0.00402

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00387 Hom.: 1

Bravo AF: 0.00220

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.00128 AC: 4

ESP6500EA AF: 0.00342 AC: 22

ExAC AF: 0.000720 AC: 43

Asia WGS AF: 0.000291 AC: 1 AN: 3452

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nemaline myopathy 6 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	KBTBD13: BS1, BS2 -

KBTBD13-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 10, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	21
Dann	Benign	0.97
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.55
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.25
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.025	D
Polyphen		0.90	P
Vest4		0.35
MVP		0.54
MPC		0.74
ClinPred		0.017	T
GERP RS		1.2
Varity_R		0.067
gMVP		0.50

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: rs201466173; hg19: chr15-65369514; COSMIC: COSV71351571; COSMIC: COSV71351571;