Genetic Variant NM_203314.3:c.643G>A (chr3-197512284-C-T) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_203314.3(BDH1):c.643G>A(p.Val215Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000631 in 1,612,816 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0034 ( 4 hom., cov: 33)

Exomes 𝑓: 0.00034 ( 2 hom. )

Consequence

BDH1
NM_203314.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 4.04

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

neurodevelopmental disorder
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

BDH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0101542175).

BP6

Variant 3-197512284-C-T is Benign according to our data. Variant chr3-197512284-C-T is described in ClinVar as Benign. ClinVar VariationId is 715597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203314.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BDH1	NM_203314.3	MANE Select	c.643G>A	p.Val215Ile	missense	Exon 8 of 8	NP_976059.1
BDH1	NM_004051.5		c.643G>A	p.Val215Ile	missense	Exon 7 of 7	NP_004042.1
BDH1	NM_203315.3		c.643G>A	p.Val215Ile	missense	Exon 7 of 7	NP_976060.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BDH1	ENST00000392379.6	TSL:5 MANE Select	c.643G>A	p.Val215Ile	missense	Exon 8 of 8	ENSP00000376184.1
BDH1	ENST00000392378.6	TSL:1	c.643G>A	p.Val215Ile	missense	Exon 7 of 7	ENSP00000376183.2
BDH1	ENST00000904000.1		c.682G>A	p.Val228Ile	missense	Exon 7 of 7	ENSP00000574059.1

Frequencies

GnomAD3 genomes

AF:

0.00342

AC:

520

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0110

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

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:

0.0000294

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.000886

AC:

220

AN:

248418

AF XY:

0.000617

show subpopulations

Gnomad AFR exome

AF:

0.0117

Gnomad AMR exome

AF:

0.000695

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000891

Gnomad OTH exome

AF:

0.000655

GnomAD4 exome

AF:

0.000341

AC:

498

AN:

1460474

Hom.:

Cov.:

AF XY:

0.000274

AC XY:

199

AN XY:

726558

show subpopulations

African (AFR)

AF:

0.0118

AC:

394

AN:

33478

American (AMR)

AF:

0.00105

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52036

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111998

Other (OTH)

AF:

0.000778

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

113

150

188

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00341

AC:

519

AN:

152342

Hom.:

Cov.:

AF XY:

0.00332

AC XY:

247

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.0110

AC:

457

AN:

41574

American (AMR)

AF:

0.00333

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68024

Other (OTH)

AF:

0.00425

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

118

147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00129

Hom.:

Bravo

AF:

0.00433

ESP6500AA

AF:

0.0132

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00101

AC:

122

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

BDH1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.42

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.079

FATHMM_MKL

Uncertain

0.89

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.34

MutationAssessor

Benign

2.0

PhyloP100

4.0

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.44

REVEL

Uncertain

0.30

Sift

Benign

0.25

Sift4G

Benign

0.23

Polyphen

0.013

Vest4

0.19

MVP

0.64

MPC

0.28

ClinPred

0.015

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.041

gMVP

0.66

Mutation Taster

=100/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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