rs138484272

Variant names:

• chr15-65076904-G-A
• rs138484272
• NM_001101362.3:c.89G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001101362.3(KBTBD13):​c.89G>A​(p.Gly30Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0044 in 1,564,574 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G30G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0033 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (47 hom.)
• Consequence: KBTBD13 NM_001101362.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.35
• Publications: 5 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]

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052545667).
• BP6: Variant 15-65076904-G-A is Benign according to our data. Variant chr15-65076904-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00452 (6381/1412236) while in subpopulation MID AF = 0.0209 (90/4296). AF 95% confidence interval is 0.0175. There are 47 homozygotes in GnomAdExome4. There are 3331 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High AC in GnomAd4 at 508 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KBTBD13	NM_001101362.3	MANE Select	c.89G>A	p.Gly30Asp	missense	Exon 1 of 1	NP_001094832.1
	RASL12	NM_001379429.1		c.-306C>T		upstream_gene	N/A	NP_001366358.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KBTBD13	ENST00000432196.5	TSL:6 MANE Select	c.89G>A	p.Gly30Asp	missense	Exon 1 of 1	ENSP00000388723.2
	RASL12	ENST00000434605.2	TSL:2	c.-306C>T		upstream_gene	N/A	ENSP00000412787.2

Frequencies

GnomAD3 genomes AF: 0.00333 AC: 507 AN: 152220 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00827

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00441

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00581 AC: 1024 AN: 176254 AF XY: 0.00633

Gnomad AFR exome AF: 0.000599

Gnomad AMR exome AF: 0.00402

Gnomad ASJ exome AF: 0.0229

Gnomad EAS exome AF: 0.0000718

Gnomad FIN exome AF: 0.000488

Gnomad NFE exome AF: 0.00513

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.00452 AC: 6381 AN: 1412236 Hom.: 47 Cov.: 29 AF XY: 0.00476 AC XY: 3331 AN XY: 699736

African (AFR) AF: 0.000979 AC: 32 AN: 32702

American (AMR) AF: 0.00439 AC: 176 AN: 40048

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 626 AN: 25512

East Asian (EAS) AF: 0.0000796 AC: 3 AN: 37690

South Asian (SAS) AF: 0.00957 AC: 775 AN: 80948

European-Finnish (FIN) AF: 0.000615 AC: 23 AN: 37404

Middle Eastern (MID) AF: 0.0209 AC: 90 AN: 4296

European-Non Finnish (NFE) AF: 0.00394 AC: 4315 AN: 1094810

Other (OTH) AF: 0.00580 AC: 341 AN: 58826

GnomAD4 genome AF: 0.00333 AC: 508 AN: 152338 Hom.: 4 Cov.: 33 AF XY: 0.00324 AC XY: 241 AN XY: 74496

African (AFR) AF: 0.000721 AC: 30 AN: 41584

American (AMR) AF: 0.00274 AC: 42 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 73 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5168

South Asian (SAS) AF: 0.00849 AC: 41 AN: 4832

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10624

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00441 AC: 300 AN: 68022

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00541 Hom.: 6

Bravo AF: 0.00334

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000255 AC: 1

ESP6500EA AF: 0.00415 AC: 34

ExAC AF: 0.00444 AC: 521

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Nemaline myopathy 6 (2)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Benign	0.89
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.69	N
PhyloP100		2.3
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	3.2	N
REVEL	Benign	0.070
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0070	B
Vest4		0.18
MVP		0.28
MPC		0.70
ClinPred		0.0051	T
GERP RS		2.6
PromoterAI		0.0074	Neutral
Varity_R		0.097
gMVP		0.47
Mutation Taster		=83/17	polymorphism

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: rs138484272; hg19: chr15-65369242;