3-197512284-C-T

Variant names:

• chr3-197512284-C-T
• rs114600793
• NM_203314.3:c.643G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_203314.3(BDH1):​c.643G>A​(p.Val215Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000631 in 1,612,816 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (2 hom.)
• Consequence: BDH1 NM_203314.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.04

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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0101542175).
• BP6: Variant 3-197512284-C-T is Benign according to our data. Variant chr3-197512284-C-T is described in ClinVar as [Benign]. Clinvar id is 715597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BDH1	NM_203314.3	c.643G>A	p.Val215Ile	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.643G>A	p.Val215Ile	missense_variant	Exon 8 of 8	5	NM_203314.3	ENSP00000376184.1

Frequencies

GnomAD3 genomes AF: 0.00342 AC: 520 AN: 152224 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

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: 0.0000294

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.000886 AC: 220 AN: 248418 AF XY: 0.000617

Gnomad AFR exome AF: 0.0117

Gnomad AMR exome AF: 0.000695

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.000655

GnomAD4 exome AF: 0.000341 AC: 498 AN: 1460474 Hom.: 2 Cov.: 31 AF XY: 0.000274 AC XY: 199 AN XY: 726558

Gnomad4 AFR exome AF: 0.0118 AC: 394 AN: 33478

Gnomad4 AMR exome AF: 0.00105 AC: 47 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: 0.0000348 AC: 3 AN: 86258

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52036

Gnomad4 NFE exome AF: 0.00000540 AC: 6 AN: 1111998

Gnomad4 Remaining exome AF: 0.000778 AC: 47 AN: 60380

GnomAD4 genome AF: 0.00341 AC: 519 AN: 152342 Hom.: 4 Cov.: 33 AF XY: 0.00332 AC XY: 247 AN XY: 74496

Gnomad4 AFR AF: 0.0110 AC: 0.0109924 AN: 0.0109924

Gnomad4 AMR AF: 0.00333 AC: 0.00333246 AN: 0.00333246

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: 0.0000294 AC: 0.0000294014 AN: 0.0000294014

Gnomad4 OTH AF: 0.00425 AC: 0.00425331 AN: 0.00425331

Alfa AF: 0.00129 Hom.: 1

Bravo AF: 0.00433

ESP6500AA AF: 0.0132 AC: 58

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00101 AC: 122

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BDH1-related disorder Benign:1

Mar 12, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T;T;T;T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.079
FATHMM_MKL	Uncertain	0.89	D
MetaRNN	Benign	0.010	T;T;T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	2.0	M;M;M;.;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.44	N;N;N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.25	T;T;T;T;T
Sift4G	Benign	0.23	T;T;T;T;T
Polyphen		0.013	B;B;B;.;.
Vest4		0.19
MVP		0.64
MPC		0.28
ClinPred		0.015	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.041
gMVP		0.66
Mutation Taster		=100/0	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: rs114600793; hg19: chr3-197239155;