chr11-47573355-C-T

Variant names:

• chr11-47573355-C-T
• rs755861672
• NM_018095.6:c.1180G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_018095.6(KBTBD4):​c.1180G>A​(p.Gly394Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,884 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: 0.000012 (0 hom.)
• Consequence: KBTBD4 NM_018095.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• Publications: 0 publications found

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]

NDUFS3 Gene-Disease associations (from GenCC):

• mitochondrial complex I deficiency, nuclear type 8

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018095.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KBTBD4	NM_018095.6	MANE Select	c.1180G>A	p.Gly394Arg	missense	Exon 4 of 4	NP_060565.4
	PTPMT1	NM_175732.3	MANE Select	c.*1726C>T		3_prime_UTR	Exon 4 of 4	NP_783859.1	Q8WUK0-1
	KBTBD4	NM_001318716.2		c.1279G>A	p.Gly427Arg	missense	Exon 4 of 4	NP_001305645.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KBTBD4	ENST00000430070.7	TSL:1 MANE Select	c.1180G>A	p.Gly394Arg	missense	Exon 4 of 4	ENSP00000415106.2	Q9NVX7-2
	KBTBD4	ENST00000533290.5	TSL:1	c.1207G>A	p.Gly403Arg	missense	Exon 3 of 3	ENSP00000436713.1	Q9NVX7-3
	PTPMT1	ENST00000326674.10	TSL:1 MANE Select	c.*1726C>T		3_prime_UTR	Exon 4 of 4	ENSP00000325958.9	Q8WUK0-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 249082 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1112006

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	0.98	L
PhyloP100		7.6
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.91	P
Vest4		0.87
MutPred		0.82		Loss of sheet (P = 0.0817)
MVP		0.92
MPC		1.1
ClinPred		0.90	D
GERP RS		5.8
Varity_R		0.57
gMVP		0.74
Mutation Taster		=49/51	disease causing

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

Other links and lift over

dbSNP: rs755861672; hg19: chr11-47594907;