Genetic Variant BDH1:c.-75G>A (chr3-197573140-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The XM_005269352.4(BDH1):c.-75G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 152,226 control chromosomes in the GnomAD database, including 2,185 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.16 ( 2185 hom., cov: 32)

Exomes 𝑓: 0.19 ( 0 hom. )

Consequence

BDH1
XM_005269352.4 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0340

Publications

10 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:

ENSG00000291091 (HGNC:):

ENSG00000291091 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein	UniProt
BDH1	XM_005269352.4 link	c.-75G>A	5_prime_UTR_variant	Exon 1 of 7	XP_005269409.1	Q02338A0A384MTY4
BDH1	NM_203315.3 link	c.-44+41G>A	intron_variant	Intron 1 of 6	NP_976060.1	Q02338A0A384MTY4
BDH1	XM_047448679.1 link	c.-2157+41G>A	intron_variant	Intron 1 of 7	XP_047304635.1
BDH1	XM_047448680.1 link	c.-3073+41G>A	intron_variant	Intron 1 of 12	XP_047304636.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
BDH1	ENST00000358186.6 link	c.-44+41G>A	intron_variant	Intron 1 of 6	5	ENSP00000350914.2	Q02338
BDH1	ENST00000431056.5 link	c.-44+41G>A	intron_variant	Intron 1 of 3	5	ENSP00000396149.1	C9JEB9
ENSG00000291091	ENST00000751206.1 link	n.1937+3503G>A	intron_variant	Intron 11 of 11
ENSG00000291091	ENST00000751207.1 link	n.1695+3503G>A	intron_variant	Intron 10 of 10

Frequencies

GnomAD3 genomes

AF:

0.156

AC:

23780

AN:

152092

Hom.:

2186

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0672

Gnomad AMI

AF:

0.258

Gnomad AMR

AF:

0.191

Gnomad ASJ

AF:

0.298

Gnomad EAS

AF:

0.0866

Gnomad SAS

AF:

0.159

Gnomad FIN

AF:

0.119

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.205

Gnomad OTH

AF:

0.177

GnomAD4 exome

AF:

0.188

AC:

AN:

Hom.:

Cov.:

AF XY:

0.250

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.500

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.143

AC:

AN:

Other (OTH)

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0183214), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.342

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.156

AC:

23776

AN:

152210

Hom.:

2185

Cov.:

AF XY:

0.151

AC XY:

11247

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.0671

AC:

2787

AN:

41534

American (AMR)

AF:

0.191

AC:

2915

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.298

AC:

1034

AN:

3470

East Asian (EAS)

AF:

0.0862

AC:

446

AN:

5174

South Asian (SAS)

AF:

0.158

AC:

762

AN:

4816

European-Finnish (FIN)

AF:

0.119

AC:

1259

AN:

10616

Middle Eastern (MID)

AF:

0.146

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.205

AC:

13925

AN:

68002

Other (OTH)

AF:

0.175

AC:

370

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

986

1972

2959

3945

4931

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

268

536

804

1072

1340

<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:

0.186

Hom.:

3278

Bravo

AF:

0.158

Asia WGS

AF:

0.115

AC:

400

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

3.4

(source)

DANN

Benign

0.73

PhyloP100

0.034

PromoterAI

-0.0053

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over