11-47578886-C-T

Variant names:

• chr11-47578886-C-T
• rs2280231
• NM_018095.6:c.19+47G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018095.6(KBTBD4):​c.19+47G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.26 in 1,550,998 control chromosomes in the GnomAD database, including 55,810 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3863 hom., cov: 31)
  • Exomes 𝑓: 0.27 (51947 hom.)
• Consequence: KBTBD4 NM_018095.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0560
• Publications: 40 publications found

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]

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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 11-47578886-C-T is Benign according to our data. Variant chr11-47578886-C-T is described in ClinVar as Benign. ClinVar VariationId is 1239179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KBTBD4	NM_018095.6	MANE Select	c.19+47G>A		intron	N/A	NP_060565.4
	KBTBD4	NM_001318723.2		c.-84G>A		5_prime_UTR	Exon 1 of 4	NP_001305652.1
	KBTBD4	NM_001318724.2		c.-84G>A		5_prime_UTR	Exon 1 of 4	NP_001305653.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KBTBD4	ENST00000430070.7	TSL:1 MANE Select	c.19+47G>A		intron	N/A	ENSP00000415106.2
	KBTBD4	ENST00000395288.6	TSL:2	c.-88G>A		5_prime_UTR	Exon 1 of 4	ENSP00000378703.2
	KBTBD4	ENST00000526005.5	TSL:5	c.-84G>A		5_prime_UTR	Exon 1 of 4	ENSP00000433340.1

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30437 AN: 151786 Hom.: 3863 Cov.: 31

Gnomad AFR AF: 0.0501

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.335

Gnomad EAS AF: 0.285

Gnomad SAS AF: 0.255

Gnomad FIN AF: 0.186

Gnomad MID AF: 0.224

Gnomad NFE AF: 0.278

Gnomad OTH AF: 0.252

GnomAD2 exomes AF: 0.241 AC: 37435 AN: 155152 AF XY: 0.250

Gnomad AFR exome AF: 0.0460

Gnomad AMR exome AF: 0.142

Gnomad ASJ exome AF: 0.331

Gnomad EAS exome AF: 0.299

Gnomad FIN exome AF: 0.184

Gnomad NFE exome AF: 0.286

Gnomad OTH exome AF: 0.277

GnomAD4 exome AF: 0.267 AC: 373575 AN: 1399090 Hom.: 51947 Cov.: 40 AF XY: 0.268 AC XY: 185113 AN XY: 690046

African (AFR) AF: 0.0434 AC: 1370 AN: 31594

American (AMR) AF: 0.148 AC: 5286 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 8501 AN: 25182

East Asian (EAS) AF: 0.240 AC: 8585 AN: 35738

South Asian (SAS) AF: 0.270 AC: 21425 AN: 79220

European-Finnish (FIN) AF: 0.187 AC: 9202 AN: 49206

Middle Eastern (MID) AF: 0.287 AC: 1578 AN: 5498

European-Non Finnish (NFE) AF: 0.280 AC: 302299 AN: 1078946

Other (OTH) AF: 0.264 AC: 15329 AN: 58002

GnomAD4 genome AF: 0.200 AC: 30423 AN: 151908 Hom.: 3863 Cov.: 31 AF XY: 0.196 AC XY: 14580 AN XY: 74224

African (AFR) AF: 0.0500 AC: 2073 AN: 41484

American (AMR) AF: 0.191 AC: 2909 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.335 AC: 1160 AN: 3466

East Asian (EAS) AF: 0.285 AC: 1470 AN: 5162

South Asian (SAS) AF: 0.255 AC: 1227 AN: 4816

European-Finnish (FIN) AF: 0.186 AC: 1960 AN: 10538

Middle Eastern (MID) AF: 0.223 AC: 65 AN: 292

European-Non Finnish (NFE) AF: 0.278 AC: 18865 AN: 67878

Other (OTH) AF: 0.249 AC: 525 AN: 2108

Alfa AF: 0.259 Hom.: 17855

Bravo AF: 0.193

Asia WGS AF: 0.238 AC: 828 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.0
DANN	Benign	0.83
PhyloP100		-0.056
PromoterAI		0.017	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2280231; hg19: chr11-47600438; COSMIC: COSV55453654; COSMIC: COSV55453654;