3-197512356-C-T

Variant names:

• chr3-197512356-C-T
• rs752035471
• NM_203314.3:c.571G>A

Variant summary

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

The NM_203314.3(BDH1):​c.571G>A​(p.Val191Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000549 in 1,603,744 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000055 (1 hom.)
• Consequence: BDH1 NM_203314.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.96

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=0.11461875).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BDH1	NM_203314.3	c.571G>A	p.Val191Ile	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.571G>A	p.Val191Ile	missense_variant	Exon 8 of 8	5	NM_203314.3	ENSP00000376184.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000119 AC: 28 AN: 235944 AF XY: 0.000155

Gnomad AFR exome AF: 0.0000635

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: 0.00000943

Gnomad OTH exome AF: 0.000339

GnomAD4 exome AF: 0.0000551 AC: 80 AN: 1451538 Hom.: 1 Cov.: 31 AF XY: 0.0000693 AC XY: 50 AN XY: 721716

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33434

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44598

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25940

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39618

Gnomad4 SAS exome AF: 0.000581 AC: 50 AN: 86040

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 46418

Gnomad4 NFE exome AF: 0.0000198 AC: 22 AN: 1109526

Gnomad4 Remaining exome AF: 0.0000997 AC: 6 AN: 60206

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74360

Gnomad4 AFR AF: 0.0000483 AC: 0.0000482556 AN: 0.0000482556

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00124 AC: 0.00124172 AN: 0.00124172

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.000140 AC: 17

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.571G>A (p.V191I) alteration is located in exon 8 (coding exon 6) of the BDH1 gene. This alteration results from a G to A substitution at nucleotide position 571, causing the valine (V) at amino acid position 191 to be replaced by an isoleucine (I). 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	0.088
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.42	T;T;T;T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.069
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.2	L;L;L;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.59	N;N;N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.19	T;T;T;T;T
Sift4G	Benign	0.10	T;T;T;T;T
Polyphen		0.46	P;P;P;.;.
Vest4		0.22
MutPred		0.59		Loss of methylation at R189 (P = 0.0827);Loss of methylation at R189 (P = 0.0827);Loss of methylation at R189 (P = 0.0827);.;.;
MVP		0.67
MPC		0.24
ClinPred		0.050	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.045
gMVP		0.62
Mutation Taster		=92/8	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: rs752035471; hg19: chr3-197239227;