13-41192583-A-G

Variant names:

• chr13-41192583-A-G
• rs1441774026
• NM_032138.7:c.1675T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032138.7(KBTBD7):​c.1675T>C​(p.Tyr559His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: KBTBD7 NM_032138.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.54

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]

ENSG00000278390 (HGNC:56824): (KBTBD6 divergent transcript)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KBTBD7	NM_032138.7	c.1675T>C	p.Tyr559His	missense_variant	Exon 1 of 1	ENST00000379483.4	NP_115514.2
KBTBD6-DT	NR_120423.1	n.350+30180A>G		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KBTBD7	ENST00000379483.4	c.1675T>C	p.Tyr559His	missense_variant	Exon 1 of 1	6	NM_032138.7	ENSP00000368797.3
ENSG00000278390	ENST00000615685.4	n.320-57A>G		intron_variant	Intron 3 of 3	4
ENSG00000278390	ENST00000619407.4	n.339+30180A>G		intron_variant	Intron 3 of 3	2
ENSG00000278390	ENST00000661006.1	n.245+30180A>G		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251452 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135896

Gnomad AFR exome AF: 0.00

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1675T>C (p.Y559H) alteration is located in exon 1 (coding exon 1) of the KBTBD7 gene. This alteration results from a T to C substitution at nucleotide position 1675, causing the tyrosine (Y) at amino acid position 559 to be replaced by a histidine (H). 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	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.0047
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.2	L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.049	B
Vest4		0.68
MutPred		0.61		Gain of disorder (P = 0.0103);
MVP		0.58
MPC		1.0
ClinPred		0.23	T
GERP RS		5.4
Varity_R		0.28
gMVP		0.58

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: rs1441774026; hg19: chr13-41766719;