19-41422747-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000709.4(BCKDHA):c.972C>T(p.Phe324Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.611 in 1,613,360 control chromosomes in the GnomAD database, including 304,365 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.66 ( 33795 hom., cov: 32)

Exomes 𝑓: 0.61 ( 270570 hom. )

Consequence

BCKDHA
NM_000709.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 2.87

Publications

40 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.22).

BP6

Variant 19-41422747-C-T is Benign according to our data. Variant chr19-41422747-C-T is described in ClinVar as [Benign]. Clinvar id is 93382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.87 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.813 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCKDHA	NM_000709.4 link	c.972C>T	p.Phe324Phe	synonymous_variant	Exon 7 of 9	ENST00000269980.7	NP_000700.1	P12694-1A0A024R0K3
BCKDHA	NM_001164783.2 link	c.969C>T	p.Phe323Phe	synonymous_variant	Exon 7 of 9		NP_001158255.1	P12694Q59EI3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCKDHA	ENST00000269980.7 link	c.972C>T	p.Phe324Phe	synonymous_variant	Exon 7 of 9	1	NM_000709.4	ENSP00000269980.2		P12694-1
ENSG00000255730	ENST00000540732.3 link	c.1074C>T	p.Phe358Phe	synonymous_variant	Exon 8 of 10	2		ENSP00000443246.1		F5H5P2

Frequencies

GnomAD3 genomes

AF:

0.656

AC:

99652

AN:

151830

Hom.:

33754

Cov.:

show subpopulations

Gnomad AFR

AF:

0.820

Gnomad AMI

AF:

0.770

Gnomad AMR

AF:

0.561

Gnomad ASJ

AF:

0.628

Gnomad EAS

AF:

0.432

Gnomad SAS

AF:

0.588

Gnomad FIN

AF:

0.659

Gnomad MID

AF:

0.636

Gnomad NFE

AF:

0.600

Gnomad OTH

AF:

0.637

GnomAD2 exomes

AF:

0.592

AC:

148372

AN:

250778

AF XY:

0.591

show subpopulations

Gnomad AFR exome

AF:

0.824

Gnomad AMR exome

AF:

0.478

Gnomad ASJ exome

AF:

0.626

Gnomad EAS exome

AF:

0.428

Gnomad FIN exome

AF:

0.657

Gnomad NFE exome

AF:

0.604

Gnomad OTH exome

AF:

0.607

GnomAD4 exome

AF:

0.606

AC:

885320

AN:

1461412

Hom.:

270570

Cov.:

AF XY:

0.605

AC XY:

439680

AN XY:

727030

show subpopulations

African (AFR)

AF:

0.831

AC:

27836

AN:

33480

American (AMR)

AF:

0.485

AC:

21676

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.624

AC:

16320

AN:

26136

East Asian (EAS)

AF:

0.459

AC:

18227

AN:

39696

South Asian (SAS)

AF:

0.582

AC:

50221

AN:

86256

European-Finnish (FIN)

AF:

0.655

AC:

34729

AN:

53028

Middle Eastern (MID)

AF:

0.636

AC:

3665

AN:

5766

European-Non Finnish (NFE)

AF:

0.608

AC:

675583

AN:

1111954

Other (OTH)

AF:

0.614

AC:

37063

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

23284

46568

69851

93135

116419

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.656

AC:

99746

AN:

151948

Hom.:

33795

Cov.:

AF XY:

0.654

AC XY:

48526

AN XY:

74252

show subpopulations

African (AFR)

AF:

0.821

AC:

34006

AN:

41442

American (AMR)

AF:

0.560

AC:

8549

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.628

AC:

2175

AN:

3466

East Asian (EAS)

AF:

0.432

AC:

2223

AN:

5142

South Asian (SAS)

AF:

0.586

AC:

2820

AN:

4810

European-Finnish (FIN)

AF:

0.659

AC:

6948

AN:

10548

Middle Eastern (MID)

AF:

0.633

AC:

186

AN:

294

European-Non Finnish (NFE)

AF:

0.600

AC:

40797

AN:

67956

Other (OTH)

AF:

0.636

AC:

1340

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1678

3355

5033

6710

8388

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.621

Hom.:

42553

Bravo

AF:

0.657

Asia WGS

AF:

0.536

AC:

1863

AN:

3478

EpiCase

AF:

0.598

EpiControl

AF:

0.603

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Jan 12, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Maple syrup urine disease

Benign:4

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jun 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Maple syrup urine disease type 1A

Benign:1

Nov 18, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

2.9

PromoterAI

-0.056

Neutral

(source)

Mutation Taster

=78/22

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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19-41422747-C-T

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