11-47573243-T-G

Position:

• chr11-47573243-T-G

Variant summary

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

The NM_018095.6(KBTBD4):​c.1292A>C​(p.Tyr431Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 7.67

Genes affected

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

PTPMT1 (HGNC:26965): (protein tyrosine phosphatase mitochondrial 1) Predicted to enable phosphatidylglycerophosphatase activity and phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity. Involved in regulation of intrinsic apoptotic signaling pathway. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

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/exons	MANE	UniProt
KBTBD4	NM_018095.6	c.1292A>C	p.Tyr431Ser	missense_variant	4/4	ENST00000430070.7
PTPMT1	NM_175732.3	c.*1614T>G		3_prime_UTR_variant	4/4	ENST00000326674.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KBTBD4	ENST00000430070.7	c.1292A>C	p.Tyr431Ser	missense_variant	4/4	1	NM_018095.6
PTPMT1	ENST00000326674.10	c.*1614T>G		3_prime_UTR_variant	4/4	1	NM_175732.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Apr 19, 2023

The c.1292A>C (p.Y431S) alteration is located in exon 4 (coding exon 4) of the KBTBD4 gene. This alteration results from a A to C substitution at nucleotide position 1292, causing the tyrosine (Y) at amino acid position 431 to be replaced by a serine (S). 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	0.32
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	T;T;T;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.74	D;D;D;D
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.34	N;.;N;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	1.3	N;N;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.19	T;T;T;T
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.77
MutPred		0.41		Gain of relative solvent accessibility (P = 0.0166);.;Gain of relative solvent accessibility (P = 0.0166);.;
MVP		0.85
MPC		0.60
ClinPred		0.82	D
GERP RS		6.0
Varity_R		0.34
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: chr11-47594795;