rs373039171

chr15-65077209-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001101362.3(KBTBD13):c.394G>A(p.Gly132Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000586 in 1,449,792 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G132G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000049 (2 hom.)
• Consequence: KBTBD13 NM_001101362.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 2.90

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.047990054).
• BP6: Variant 15-65077209-G-A is Benign according to our data. Variant chr15-65077209-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 316741.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000138 (21/151950) while in subpopulation EAS AF= 0.000579 (3/5178). AF 95% confidence interval is 0.000261. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KBTBD13	NM_001101362.3	c.394G>A	p.Gly132Ser	missense_variant	1/1	ENST00000432196.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KBTBD13	ENST00000432196.5	c.394G>A	p.Gly132Ser	missense_variant	1/1		NM_001101362.3	P1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 151950 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000532 AC: 4 AN: 75162 Hom.: 1 AF XY: 0.0000233 AC XY: 1 AN XY: 42856

Gnomad AFR exome AF: 0.000942

Gnomad AMR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.0000493 AC: 64 AN: 1297842 Hom.: 2 Cov.: 41 AF XY: 0.0000315 AC XY: 20 AN XY: 634406

Gnomad4 AFR exome AF: 0.000231

Gnomad4 AMR exome AF: 0.0000413

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000168

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000386

Gnomad4 OTH exome AF: 0.000894

GnomAD4 genome AF: 0.000138 AC: 21 AN: 151950 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74244

Gnomad4 AFR AF: 0.000410

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000144

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nemaline myopathy 6 Uncertain:1 Benign:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2022

The c.394G>A (p.G132S) alteration is located in exon 1 (coding exon 1) of the KBTBD13 gene. This alteration results from a G to A substitution at nucleotide position 394, causing the glycine (G) at amino acid position 132 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	18
Dann	Benign	0.91
DEOGEN2	Benign	0.0031	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.062
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.61	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.92	L
MutationTaster	Benign	0.79	N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.20
Sift	Benign	0.76	T
Sift4G	Benign	0.72	T
Polyphen		0.11	B
Vest4		0.086
MutPred		0.43		Gain of phosphorylation at G132 (P = 0.0612);
MVP		0.57
MPC		0.53
ClinPred		0.035	T
GERP RS		4.6
Varity_R		0.077
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs373039171; hg19: chr15-65369547;