13-41192472-T-C

Variant names:

• chr13-41192472-T-C
• rs368581328
• NM_032138.7:c.1786A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032138.7(KBTBD7):​c.1786A>G​(p.Ile596Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I596L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KBTBD7 NM_032138.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.643
• Publications: 0 publications found

Genes affected

KBTBD7 (HGNC:25266): (kelch repeat and BTB domain containing 7) The protein encoded by this gene is a transcriptional activator, having been shown to increase the transcription of activator protein-1 and serum response element. The encoded protein can also form a complex with KBTBD6 and CUL3, which regulates the ubiquitylation and degradation of TIAM1, which is a regulator of RAC1. [provided by RefSeq, Jul 2016]

KBTBD6-DT (HGNC:56824): (KBTBD6 divergent transcript)

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10491517).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032138.7. 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
	KBTBD7	NM_032138.7	MANE Select	c.1786A>G	p.Ile596Val	missense	Exon 1 of 1	NP_115514.2
	KBTBD6-DT	NR_120423.1		n.350+30069T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KBTBD7	ENST00000379483.4	TSL:6 MANE Select	c.1786A>G	p.Ile596Val	missense	Exon 1 of 1	ENSP00000368797.3	Q8WVZ9
	KBTBD6-DT	ENST00000615685.4	TSL:4	n.320-168T>C		intron	N/A
	KBTBD6-DT	ENST00000619407.4	TSL:2	n.339+30069T>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	12
DANN	Benign	0.85
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.64
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.030
Sift	Benign	0.40	T
Sift4G	Benign	0.90	T
Polyphen		0.0010	B
Vest4		0.055
MutPred		0.34		Loss of sheet (P = 0.1158)
MVP		0.44
MPC		0.57
ClinPred		0.081	T
GERP RS		1.7
Varity_R		0.035
gMVP		0.042
Mutation Taster		=73/27	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: rs368581328; hg19: chr13-41766608;