dbSNP rs2280231: KBTBD4:c.19+47G>A (chr11-47578886-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0560

Publications

40 publications found

Variant links:

Genes affected

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

KBTBD4 links:

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

NDUFS3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KBTBD4	NM_018095.6 link	c.19+47G>A		intron_variant	Intron 1 of 3	ENST00000430070.7	NP_060565.4
NDUFS3	NM_004551.3 link	c.-206C>T		upstream_gene_variant		ENST00000263774.9	NP_004542.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KBTBD4	ENST00000430070.7 link	c.19+47G>A		intron_variant	Intron 1 of 3	1	NM_018095.6	ENSP00000415106.2
NDUFS3	ENST00000263774.9 link	c.-206C>T		upstream_gene_variant		1	NM_004551.3	ENSP00000263774.4

Frequencies

GnomAD3 genomes

AF:

0.201

AC:

30437

AN:

151786

Hom.:

3863

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.268

AC XY:

185113

AN XY:

690046

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

16422

32843

49265

65686

82108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10094

20188

30282

40376

50470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.200

AC:

30423

AN:

151908

Hom.:

3863

Cov.:

AF XY:

0.196

AC XY:

14580

AN XY:

74224

show subpopulations

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:

AN:

292

European-Non Finnish (NFE)

AF:

0.278

AC:

18865

AN:

67878

Other (OTH)

AF:

0.249

AC:

525

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1133

2265

3398

4530

5663

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

332

664

996

1328

1660

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

LINK: link

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

6.0

(source)

DANN

Benign

0.83

PhyloP100

-0.056

PromoterAI

0.017

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over