Genetic Variant BDH1:p.Arg205Cys (chr3-197512314-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_203314.3(BDH1):c.613C>T(p.Arg205Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000745 in 1,611,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R205G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

BDH1
NM_203314.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.70

Variant links:

Genes affected

BDH1 (HGNC:1027): (3-hydroxybutyrate dehydrogenase 1) This gene encodes a member of the short-chain dehydrogenase/reductase gene family. The encoded protein forms a homotetrameric lipid-requiring enzyme of the mitochondrial membrane and has a specific requirement for phosphatidylcholine for optimal enzymatic activity. The encoded protein catalyzes the interconversion of acetoacetate and (R)-3-hydroxybutyrate, the two major ketone bodies produced during fatty acid catabolism. Alternatively spliced transcript variants encoding the same protein have been described. [provided by RefSeq, Jul 2008]

BDH1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BDH1	NM_203314.3 link	c.613C>T	p.Arg205Cys	missense_variant	Exon 8 of 8	ENST00000392379.6	NP_976059.1	Q02338A0A384MTY4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BDH1	ENST00000392379.6 link	c.613C>T	p.Arg205Cys	missense_variant	Exon 8 of 8	5	NM_203314.3	ENSP00000376184.1		Q02338

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000123

AC:

AN:

244662

AF XY:

0.00000753

show subpopulations

Gnomad AFR exome

AF:

0.000188

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000754

AC:

AN:

1458998

Hom.:

Cov.:

AF XY:

0.00000827

AC XY:

AN XY:

725856

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

AC:

AN:

33478

Gnomad4 AMR exome

AF:

0.0000224

AC:

AN:

44710

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26130

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39698

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

86254

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

50658

Gnomad4 NFE exome

AF:

0.00000540

AC:

AN:

1111938

Gnomad4 Remaining exome

AF:

0.0000331

AC:

AN:

60364

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<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:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.0000654

AC:

0.000065445

AN:

0.000065445

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 26, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.613C>T (p.R205C) alteration is located in exon 8 (coding exon 6) of the BDH1 gene. This alteration results from a C to T substitution at nucleotide position 613, causing the arginine (R) at amino acid position 205 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Uncertain

0.035

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

D;D;D;D;.

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.92

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.83

D;D;D;D;D

MetaSVM

Uncertain

0.33

MutationAssessor

Benign

1.5

L;L;L;.;.

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-4.6

D;D;D;D;D

REVEL

Pathogenic

0.69

Sift

Uncertain

0.016

D;D;D;D;T

Sift4G

Benign

0.12

T;T;T;T;T

Polyphen

1.0

D;D;D;.;.

Vest4

0.68

MVP

0.96

MPC

1.0

ClinPred

0.89

GERP RS

3.5

Varity_R

0.29

gMVP

0.89

Mutation Taster

=77/23

polymorphism

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over