3-197514412-C-G

Variant names:

• chr3-197514412-C-G
• rs78687894
• NM_203314.3:c.414G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_203314.3(BDH1):​c.414G>C​(p.Met138Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BDH1 NM_203314.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.33
• Publications: 4 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24161255).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BDH1	NM_203314.3	c.414G>C	p.Met138Ile	missense_variant	Exon 7 of 8	ENST00000392379.6	NP_976059.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BDH1	ENST00000392379.6	c.414G>C	p.Met138Ile	missense_variant	Exon 7 of 8	5	NM_203314.3	ENSP00000376184.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T;T;T;T;.;T;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.24	T;T;T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	-1.8	N;N;N;.;.;.;.
PhyloP100		1.3
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.020	N;N;N;N;N;N;N
REVEL	Uncertain	0.29
Sift	Benign	0.064	T;T;T;D;T;D;D
Sift4G	Uncertain	0.026	D;D;D;D;D;.;.
Polyphen		0.0	B;B;B;.;.;.;.
Vest4		0.48
MutPred		0.70		Loss of disorder (P = 0.1014);Loss of disorder (P = 0.1014);Loss of disorder (P = 0.1014);.;.;.;Loss of disorder (P = 0.1014);
MVP		0.66
MPC		0.28
ClinPred		0.57	D
GERP RS		4.1
PromoterAI		0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.52
Mutation Taster		=94/6	polymorphism

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: rs78687894; hg19: chr3-197241283;