Genetic Variant BDH1:p.Arg174Gln (chr3-197514305-C-T) – 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.521G>A(p.Arg174Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000253 in 1,461,622 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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

BDH1
NM_203314.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.03

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:

Genome browser will be placed here

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, 0.771

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BDH1	NM_203314.3 link	c.521G>A	p.Arg174Gln	missense_variant	Exon 7 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.521G>A	p.Arg174Gln	missense_variant	Exon 7 of 8	5	NM_203314.3	ENSP00000376184.1		Q02338

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251148

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1461622

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

33470

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

44692

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26128

Gnomad4 EAS exome

AF:

0.000101

AC:

AN:

39676

Gnomad4 SAS exome

AF:

0.0000580

AC:

AN:

86230

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53416

Gnomad4 NFE exome

AF:

0.0000234

AC:

AN:

1111868

Gnomad4 Remaining exome

AF:

0.0000166

AC:

AN:

60376

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

Cov.:

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 01, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.521G>A (p.R174Q) alteration is located in exon 7 (coding exon 5) of the BDH1 gene. This alteration results from a G to A substitution at nucleotide position 521, causing the arginine (R) at amino acid position 174 to be replaced by a glutamine (Q). 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

Benign

0.10

BayesDel_addAF

Uncertain

0.012

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.76

D;D;D;T;.;D;D

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.91

M_CAP

Benign

0.064

MetaRNN

Pathogenic

0.77

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.38

MutationAssessor

Uncertain

2.1

M;M;M;.;.;.;.

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-2.7

D;D;D;N;N;D;D

REVEL

Uncertain

0.62

Sift

Uncertain

0.020

D;D;D;D;D;T;T

Sift4G

Uncertain

0.054

T;T;T;T;T;.;.

Polyphen

0.99

D;D;D;.;.;.;.

Vest4

0.54

MutPred

0.67

Loss of MoRF binding (P = 0.0155);Loss of MoRF binding (P = 0.0155);Loss of MoRF binding (P = 0.0155);.;.;.;Loss of MoRF binding (P = 0.0155);

MVP

0.95

MPC

0.40

ClinPred

0.56

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.24

gMVP

0.82

Mutation Taster

=83/17

polymorphism

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

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