15-65077105-T-C

Variant names:

• chr15-65077105-T-C
• rs767384093
• NM_001101362.3:c.290T>C

Variant summary

Our verdict is Uncertain significance. The variant received 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 Uncertain significance.

• 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:3 B:1
• Conservation: PhyloP100: 4.80
• Publications: 1 publications found

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]

KBTBD13 Gene-Disease associations (from GenCC):

• nemaline myopathy 6

  Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• BS2: High AC in GnomAd4 at 9 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001101362.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KBTBD13	NM_001101362.3	MANE Select	c.290T>C	p.Leu97Pro	missense	Exon 1 of 1	NP_001094832.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KBTBD13	ENST00000432196.5	TSL:6 MANE Select	c.290T>C	p.Leu97Pro	missense	Exon 1 of 1	ENSP00000388723.2

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

GnomAD2 exomes AF: 0.0000742 AC: 9 AN: 121256 AF XY: 0.0000746

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 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

African (AFR) AF: 0.00 AC: 0 AN: 29480

American (AMR) AF: 0.000290 AC: 10 AN: 34506

Ashkenazi Jewish (ASJ) AF: 0.0000407 AC: 1 AN: 24576

East Asian (EAS) AF: 0.00 AC: 0 AN: 34448

South Asian (SAS) AF: 0.0000643 AC: 5 AN: 77744

European-Finnish (FIN) AF: 0.0000277 AC: 1 AN: 36138

Middle Eastern (MID) AF: 0.000179 AC: 1 AN: 5596

European-Non Finnish (NFE) AF: 0.0000439 AC: 47 AN: 1071780

Other (OTH) AF: 0.0000526 AC: 3 AN: 57040

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

African (AFR) AF: 0.0000723 AC: 3 AN: 41484

American (AMR) AF: 0.000196 AC: 3 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67948

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000127 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	1	Nemaline myopathy 6 (3)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		4.8
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
PromoterAI		0.068	Neutral
Varity_R		0.96
gMVP		0.96
Mutation Taster		=37/63	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs767384093; hg19: chr15-65369443;