3-197512343-C-G

Position:

• chr3-197512343-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_203314.3(BDH1):​c.584G>C​(p.Ser195Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,455,448 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: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: BDH1 NM_203314.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.80

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity BDH_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.923

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BDH1	NM_203314.3	c.584G>C	p.Ser195Thr	missense_variant	8/8	ENST00000392379.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BDH1	ENST00000392379.6	c.584G>C	p.Ser195Thr	missense_variant	8/8	5	NM_203314.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000832 AC: 2 AN: 240418 Hom.: 0 AF XY: 0.00000764 AC XY: 1 AN XY: 130852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000185

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000254 AC: 37 AN: 1455448 Hom.: 0 Cov.: 31 AF XY: 0.0000235 AC XY: 17 AN XY: 723824

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000151

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;D;D;D;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;H;H;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.9	D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.027	D;D;D;D;D
Sift4G	Uncertain	0.029	D;D;D;D;D
Polyphen		1.0	D;D;D;.;.
Vest4		0.80
MVP		1.0
MPC		0.83
ClinPred		0.96	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.53
gMVP		0.94

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

Other links and lift over

dbSNP: rs964914209; hg19: chr3-197239214;