NM_000709.4:c.995+26C>T

Variant names:

Variant summary

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

The NM_000709.4(BCKDHA):c.995+26C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.414 in 1,611,234 control chromosomes in the GnomAD database, including 144,759 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 11350 hom., cov: 33)

Exomes 𝑓: 0.42 ( 133409 hom. )

Consequence

BCKDHA
NM_000709.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.248

Publications

20 publications found

Variant links:

Genes affected

BCKDHA (HGNC:986): (branched chain keto acid dehydrogenase E1 subunit alpha) The branched-chain alpha-keto acid (BCAA) dehydrogenase (BCKD) complex is an innter mitochondrial enzyme complex that catalyzes the second major step in the catabolism of the branched-chain amino acids leucine, isoleucine, and valine. The BCKD complex consists of three catalytic components: a heterotetrameric (alpha2-beta2) branched-chain alpha-keto acid decarboxylase (E1), a dihydrolipoyl transacylase (E2), and a dihydrolipoamide dehydrogenase (E3). This gene encodes the alpha subunit of the decarboxylase (E1) component. Mutations in this gene result in maple syrup urine disease, type IA. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

BCKDHA Gene-Disease associations (from GenCC):

maple syrup urine disease
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
maple syrup urine disease type 1A
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P, Myriad Women’s Health, ClinGen
classic maple syrup urine disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
intermediate maple syrup urine disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
intermittent maple syrup urine disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
thiamine-responsive maple syrup urine disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

BCKDHA links:

ENSG00000255730 (HGNC:):

ENSG00000255730 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=-0.86).

BP6

Variant 19-41422796-C-T is Benign according to our data. Variant chr19-41422796-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.44 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCKDHA	NM_000709.4 link	c.995+26C>T		intron_variant	Intron 7 of 8	ENST00000269980.7	NP_000700.1	P12694-1A0A024R0K3
BCKDHA	NM_001164783.2 link	c.992+26C>T		intron_variant	Intron 7 of 8		NP_001158255.1	P12694Q59EI3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCKDHA	ENST00000269980.7 link	c.995+26C>T		intron_variant	Intron 7 of 8	1	NM_000709.4	ENSP00000269980.2		P12694-1
ENSG00000255730	ENST00000540732.3 link	c.1097+26C>T		intron_variant	Intron 8 of 9	2		ENSP00000443246.1		F5H5P2

Frequencies

GnomAD3 genomes

AF:

0.370

AC:

56258

AN:

151864

Hom.:

11354

Cov.:

show subpopulations

Gnomad AFR

AF:

0.255

Gnomad AMI

AF:

0.541

Gnomad AMR

AF:

0.359

Gnomad ASJ

AF:

0.402

Gnomad EAS

AF:

0.0832

Gnomad SAS

AF:

0.256

Gnomad FIN

AF:

0.527

Gnomad MID

AF:

0.418

Gnomad NFE

AF:

0.445

Gnomad OTH

AF:

0.376

GnomAD2 exomes

AF:

0.374

AC:

92865

AN:

248348

AF XY:

0.375

show subpopulations

Gnomad AFR exome

AF:

0.252

Gnomad AMR exome

AF:

0.341

Gnomad ASJ exome

AF:

0.410

Gnomad EAS exome

AF:

0.0804

Gnomad FIN exome

AF:

0.519

Gnomad NFE exome

AF:

0.445

Gnomad OTH exome

AF:

0.408

GnomAD4 exome

AF:

0.419

AC:

611443

AN:

1459252

Hom.:

133409

Cov.:

AF XY:

0.416

AC XY:

301827

AN XY:

725952

show subpopulations

African (AFR)

AF:

0.248

AC:

8293

AN:

33474

American (AMR)

AF:

0.340

AC:

15201

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.415

AC:

10837

AN:

26132

East Asian (EAS)

AF:

0.0706

AC:

2801

AN:

39694

South Asian (SAS)

AF:

0.278

AC:

23985

AN:

86244

European-Finnish (FIN)

AF:

0.516

AC:

26500

AN:

51404

Middle Eastern (MID)

AF:

0.397

AC:

2289

AN:

5768

European-Non Finnish (NFE)

AF:

0.448

AC:

497791

AN:

1111512

Other (OTH)

AF:

0.394

AC:

23746

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

19882

39764

59645

79527

99409

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14652

29304

43956

58608

73260

<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:

0.370

AC:

56257

AN:

151982

Hom.:

11350

Cov.:

AF XY:

0.369

AC XY:

27416

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.254

AC:

10547

AN:

41456

American (AMR)

AF:

0.359

AC:

5486

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.402

AC:

1392

AN:

3464

East Asian (EAS)

AF:

0.0836

AC:

432

AN:

5170

South Asian (SAS)

AF:

0.256

AC:

1232

AN:

4820

European-Finnish (FIN)

AF:

0.527

AC:

5558

AN:

10542

Middle Eastern (MID)

AF:

0.412

AC:

121

AN:

294

European-Non Finnish (NFE)

AF:

0.445

AC:

30206

AN:

67940

Other (OTH)

AF:

0.374

AC:

792

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1751

3502

5253

7004

8755

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

538

1076

1614

2152

2690

<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:

0.411

Hom.:

18275

Bravo

AF:

0.357

Asia WGS

AF:

0.186

AC:

651

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Aug 23, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jun 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Maple syrup urine disease

Benign:1

Jun 10, 2021

Genome-Nilou Lab

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

-0.86

CADD

Benign

0.74

(source)

DANN

Benign

0.80

PhyloP100

-0.25

PromoterAI

-0.043

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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