chr11-47577829-C-A

Position:

• chr11-47577829-C-A

Variant summary

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

The NM_018095.6(KBTBD4):​c.219G>T​(p.Gln73His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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: KBTBD4 NM_018095.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.13

Genes affected

KBTBD4 (HGNC:23761): (kelch repeat and BTB domain containing 4)

(HGNC:):

NDUFS3 (HGNC:7710): (NADH:ubiquinone oxidoreductase core subunit S3) This gene encodes one of the iron-sulfur protein (IP) components of mitochondrial NADH:ubiquinone oxidoreductase (complex I). Mutations in this gene are associated with Leigh syndrome resulting from mitochondrial complex I deficiency.[provided by RefSeq, Apr 2009]

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=0.2778061).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KBTBD4	NM_018095.6	c.219G>T	p.Gln73His	missense_variant	2/4	ENST00000430070.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KBTBD4	ENST00000430070.7	c.219G>T	p.Gln73His	missense_variant	2/4	1	NM_018095.6
	ENST00000450908.2	n.105C>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Nov 05, 2021

The c.219G>T (p.Q73H) alteration is located in exon 2 (coding exon 2) of the KBTBD4 gene. This alteration results from a G to T substitution at nucleotide position 219, causing the glutamine (Q) at amino acid position 73 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	Benign	0.12
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T;T;T;.;T;T;T;.;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.75	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.54	N;.;N;.;.;.;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.43	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.044
Sift	Benign	0.079	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.25	T;T;T;T;T;.;T;T;.
Polyphen		0.0010	B;.;B;B;.;.;.;.;.
Vest4		0.26
MutPred		0.51		Gain of sheet (P = 0.1945);.;Gain of sheet (P = 0.1945);.;.;Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);.;
MVP		0.46
MPC		0.29
ClinPred		0.70	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.096
gMVP		0.39

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: chr11-47599381;