11-106054016-G-A

Position:

• chr11-106054016-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198439.3(KBTBD3):​c.673C>T​(p.His225Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KBTBD3 NM_198439.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.09

Genes affected

KBTBD3 (HGNC:22934): (kelch repeat and BTB domain containing 3)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17887142).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KBTBD3	NM_198439.3	c.673C>T	p.His225Tyr	missense_variant	4/4	ENST00000531837.2	NP_940841.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KBTBD3	ENST00000531837.2	c.673C>T	p.His225Tyr	missense_variant	4/4	1	NM_198439.3	ENSP00000432163	P1
KBTBD3	ENST00000526793.5	c.673C>T	p.His225Tyr	missense_variant	3/3	1		ENSP00000436262	P1
KBTBD3	ENST00000534815.1	c.436C>T	p.His146Tyr	missense_variant	2/2	5		ENSP00000431910

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461460 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727022

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2023

The c.673C>T (p.H225Y) alteration is located in exon 4 (coding exon 2) of the KBTBD3 gene. This alteration results from a C to T substitution at nucleotide position 673, causing the histidine (H) at amino acid position 225 to be replaced by a tyrosine (Y). 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	0.064
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Benign	0.94
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.031
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.74	T;.;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.1	D;N;N
REVEL	Benign	0.11
Sift	Benign	0.17	T;T;T
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.18
MVP		0.67
MPC		0.18
ClinPred		0.60	D
GERP RS		3.6
gMVP		0.51

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: rs1860495898; hg19: chr11-105924743;