3-197512286-C-G

Variant names:

• chr3-197512286-C-G
• rs144830970
• NM_203314.3:c.641G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_203314.3(BDH1):​c.641G>C​(p.Gly214Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000769 in 1,612,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G214R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: BDH1 NM_203314.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.06

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08181235).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BDH1	NM_203314.3	c.641G>C	p.Gly214Ala	missense_variant	Exon 8 of 8	ENST00000392379.6	NP_976059.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BDH1	ENST00000392379.6	c.641G>C	p.Gly214Ala	missense_variant	Exon 8 of 8	5	NM_203314.3	ENSP00000376184.1

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

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: 0.00

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000109 AC: 27 AN: 248342 AF XY: 0.0000892

Gnomad AFR exome AF: 0.00143

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000349 AC: 51 AN: 1460468 Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17 AN XY: 726558

Gnomad4 AFR exome AF: 0.00111 AC: 37 AN: 33478

Gnomad4 AMR exome AF: 0.000157 AC: 7 AN: 44720

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86258

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52032

Gnomad4 NFE exome AF: 8.99e-7 AC: 1 AN: 1111998

Gnomad4 Remaining exome AF: 0.0000994 AC: 6 AN: 60378

GnomAD4 genome AF: 0.000479 AC: 73 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.000510 AC XY: 38 AN XY: 74490

Gnomad4 AFR AF: 0.00149 AC: 0.0014916 AN: 0.0014916

Gnomad4 AMR AF: 0.000588 AC: 0.000587928 AN: 0.000587928

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.000945 AC: 0.00094518 AN: 0.00094518

Alfa AF: 0.0000563 Hom.: 0

Bravo AF: 0.000627

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000132 AC: 16

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 03, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.641G>C (p.G214A) alteration is located in exon 8 (coding exon 6) of the BDH1 gene. This alteration results from a G to C substitution at nucleotide position 641, causing the glycine (G) at amino acid position 214 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	0.0084	T
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Uncertain	0.74	D;D;D;D;.
Eigen	Benign	-0.022
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.082	T;T;T;T;T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	-0.69	N;N;N;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.2	D;D;D;D;D
REVEL	Uncertain	0.56
Sift	Benign	0.51	T;T;T;T;T
Sift4G	Benign	0.36	T;T;T;T;T
Polyphen		0.27	B;B;B;.;.
Vest4		0.35
MVP		0.94
MPC		0.85
ClinPred		0.072	T
GERP RS		5.3
Varity_R		0.24
gMVP		0.91
Mutation Taster		=54/46	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

Publications

LitVar

Other links and lift over

dbSNP: rs144830970; hg19: chr3-197239157;