11-106053043-A-T

Position:

• chr11-106053043-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_198439.3(KBTBD3):​c.1646T>A​(p.Ile549Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KBTBD3 NM_198439.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.99

Genes affected

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

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KBTBD3	NM_198439.3	c.1646T>A	p.Ile549Asn	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.1646T>A	p.Ile549Asn	missense_variant	4/4	1	NM_198439.3	ENSP00000432163	P1
KBTBD3	ENST00000526793.5	c.1646T>A	p.Ile549Asn	missense_variant	3/3	1		ENSP00000436262	P1
KBTBD3	ENST00000534815.1	c.1409T>A	p.Ile470Asn	missense_variant	2/2	5		ENSP00000431910

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461446 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727018

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Jan 23, 2023

The c.1646T>A (p.I549N) alteration is located in exon 4 (coding exon 2) of the KBTBD3 gene. This alteration results from a T to A substitution at nucleotide position 1646, causing the isoleucine (I) at amino acid position 549 to be replaced by an asparagine (N). 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	Uncertain	0.44
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	0.98
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D;.;D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Uncertain	-0.027	T
MutationTaster	Benign	0.84	D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.015	D;D;D
Vest4		0.78
MVP		0.93
MPC		0.48
ClinPred		0.91	D
GERP RS		6.0
gMVP		0.59

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: rs1860455778; hg19: chr11-105923770;