chr3-67004007-G-T

Position:

• chr3-67004007-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032505.3(KBTBD8):​c.1040G>T​(p.Ser347Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 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)
• Consequence: KBTBD8 NM_032505.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.99

Genes affected

KBTBD8 (HGNC:30691): (kelch repeat and BTB domain containing 8) Involved in neural crest cell development; neural crest formation; and protein monoubiquitination. Part of Cul3-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3972633).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KBTBD8	NM_032505.3	c.1040G>T	p.Ser347Ile	missense_variant	3/4	ENST00000417314.2	NP_115894.2
KBTBD8	XM_005264771.4	c.809G>T	p.Ser270Ile	missense_variant	2/3		XP_005264828.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KBTBD8	ENST00000417314.2	c.1040G>T	p.Ser347Ile	missense_variant	3/4	2	NM_032505.3	ENSP00000401878.2
KBTBD8	ENST00000460576.5	c.17-3915G>T		intron_variant		2		ENSP00000419738.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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

Jan 26, 2022

The c.1040G>T (p.S347I) alteration is located in exon 3 (coding exon 3) of the KBTBD8 gene. This alteration results from a G to T substitution at nucleotide position 1040, causing the serine (S) at amino acid position 347 to be replaced by an isoleucine (I). 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	0.18
BayesDel_addAF	Benign	0.0011	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	0.95	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.20
Sift	Benign	0.039	D
Sift4G	Uncertain	0.021	D
Polyphen		0.96	D
Vest4		0.42
MutPred		0.46		Gain of glycosylation at S346 (P = 0.0076);
MVP		0.84
MPC		0.53
ClinPred		0.81	D
GERP RS		5.3
Varity_R		0.19
gMVP		0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-67054431;