11-47573784-C-T

Variant names:

• chr11-47573784-C-T
• rs1267204796
• NM_018095.6:c.751G>A

Variant summary

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

The NM_018095.6(KBTBD4):​c.751G>A​(p.Gly251Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000282 in 1,417,014 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: KBTBD4 NM_018095.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.48

Genes affected

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

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 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
KBTBD4	NM_018095.6	c.751G>A	p.Gly251Arg	missense_variant	Exon 4 of 4	ENST00000430070.7	NP_060565.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KBTBD4	ENST00000430070.7	c.751G>A	p.Gly251Arg	missense_variant	Exon 4 of 4	1	NM_018095.6	ENSP00000415106.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000885 AC: 2 AN: 226048 Hom.: 0 AF XY: 0.0000162 AC XY: 2 AN XY: 123224

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: 0.0000188

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000282 AC: 4 AN: 1417014 Hom.: 0 Cov.: 31 AF XY: 0.00000429 AC XY: 3 AN XY: 699602

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: 0.00000275

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.751G>A (p.G251R) alteration is located in exon 4 (coding exon 4) of the KBTBD4 gene. This alteration results from a G to A substitution at nucleotide position 751, causing the glycine (G) at amino acid position 251 to be replaced by an arginine (R). 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	0.68
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	T;T;T;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.74	D;D;D;D
MetaSVM	Uncertain	-0.0050	T
MutationAssessor	Uncertain	2.1	M;.;M;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	1.4	N;N;N;N
REVEL	Uncertain	0.52
Sift	Benign	0.35	T;T;T;T
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.81
MutPred		0.57		Gain of MoRF binding (P = 0.0496);.;Gain of MoRF binding (P = 0.0496);.;
MVP		0.93
MPC		0.61
ClinPred		0.39	T
GERP RS		5.6
Varity_R		0.20
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs1267204796; hg19: chr11-47595336;