NM_000709.4:c.972C>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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000709.4. 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
	BCKDHA	NM_000709.4	MANE Select	c.972C>T	p.Phe324Phe	synonymous	Exon 7 of 9	NP_000700.1
	BCKDHA	NM_001164783.2		c.969C>T	p.Phe323Phe	synonymous	Exon 7 of 9	NP_001158255.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BCKDHA	ENST00000269980.7	TSL:1 MANE Select	c.972C>T	p.Phe324Phe	synonymous	Exon 7 of 9	ENSP00000269980.2
ENSG00000255730	ENST00000540732.3	TSL:2	c.1074C>T	p.Phe358Phe	synonymous	Exon 8 of 10	ENSP00000443246.1
BCKDHA	ENST00000919033.1		c.1200C>T	p.Phe400Phe	synonymous	Exon 8 of 10	ENSP00000589092.1

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

Age Distribution

Exome Het

Exome Hom

Variant carriers

18282

36564

54846

73128

91410

<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:

0.656

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

Age Distribution

Genome Het

Genome Hom

Variant carriers

788

1576

2364

3152

3940

<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:

0.621

Hom.:

42553

Bravo

AF:

0.657

Asia WGS

AF:

0.536

AC:

1863

AN:

3478

EpiCase

AF:

0.598

EpiControl

AF:

0.603

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Maple syrup urine disease (4)

not specified (4)

not provided (2)

Maple syrup urine disease type 1A (1)

Computational scores

Source: dbNSFP v4.9

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over