NM_203314.3:c.587T>C

Variant names:

• chr3-197512340-A-G
• rs1275748164
• NM_203314.3:c.587T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_203314.3(BDH1):​c.587T>C​(p.Met196Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,392 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BDH1 NM_203314.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.20
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BDH1	NM_203314.3	MANE Select	c.587T>C	p.Met196Thr	missense	Exon 8 of 8	NP_976059.1
	BDH1	NM_004051.5		c.587T>C	p.Met196Thr	missense	Exon 7 of 7	NP_004042.1
	BDH1	NM_203315.3		c.587T>C	p.Met196Thr	missense	Exon 7 of 7	NP_976060.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BDH1	ENST00000392379.6	TSL:5 MANE Select	c.587T>C	p.Met196Thr	missense	Exon 8 of 8	ENSP00000376184.1
	BDH1	ENST00000392378.6	TSL:1	c.587T>C	p.Met196Thr	missense	Exon 7 of 7	ENSP00000376183.2
	BDH1	ENST00000904000.1		c.626T>C	p.Met209Thr	missense	Exon 7 of 7	ENSP00000574059.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000415 AC: 1 AN: 240882 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000925

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456392 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724400

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111270

Other (OTH) AF: 0.00 AC: 0 AN: 60326

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	23
DANN	Benign	0.94
DEOGEN2	Uncertain	0.65	D
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	0.045	N
PhyloP100		9.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.5	N
REVEL	Pathogenic	0.65
Sift	Benign	0.12	T
Sift4G	Benign	0.23	T
Polyphen		0.42	B
Vest4		0.64
MutPred		0.54		Gain of glycosylation at S195 (P = 0.0629)
MVP		0.94
MPC		0.59
ClinPred		0.60	D
GERP RS		5.3
Varity_R		0.32
gMVP		0.89
Mutation Taster		=42/58	disease causing

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

Other links and lift over

dbSNP: rs1275748164; hg19: chr3-197239211;