3-197511986-C-T

Variant names:

• chr3-197511986-C-T
• rs144840608
• NM_203314.3:c.941G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 1P and 7B. PP3 BP4_Moderate BP6 BS2

The NM_203314.3(BDH1):​c.941G>A​(p.Arg314His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,611,480 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (5 hom.)
• Consequence: BDH1 NM_203314.3 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 7.91

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 -6 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.21549278).
• BP6: Variant 3-197511986-C-T is Benign according to our data. Variant chr3-197511986-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3052892.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BDH1	NM_203314.3	c.941G>A	p.Arg314His	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.941G>A	p.Arg314His	missense_variant	Exon 8 of 8	5	NM_203314.3	ENSP00000376184.1

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 171 AN: 152106 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.00228

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.000958 AC: 238 AN: 248542 AF XY: 0.000947

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.000103

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000328

Gnomad NFE exome AF: 0.00194

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.00148 AC: 2164 AN: 1459374 Hom.: 5 Cov.: 31 AF XY: 0.00145 AC XY: 1049 AN XY: 725756

Gnomad4 AFR exome AF: 0.000269 AC: 9 AN: 33474

Gnomad4 AMR exome AF: 0.000202 AC: 9 AN: 44614

Gnomad4 ASJ exome AF: 0.000155 AC: 4 AN: 25802

Gnomad4 EAS exome AF: 0.0000504 AC: 2 AN: 39698

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 85778

Gnomad4 FIN exome AF: 0.000338 AC: 18 AN: 53268

Gnomad4 NFE exome AF: 0.00187 AC: 2082 AN: 1110670

Gnomad4 Remaining exome AF: 0.000663 AC: 40 AN: 60310

GnomAD4 genome AF: 0.00112 AC: 171 AN: 152106 Hom.: 0 Cov.: 33 AF XY: 0.00104 AC XY: 77 AN XY: 74312

Gnomad4 AFR AF: 0.000242 AC: 0.000241581 AN: 0.000241581

Gnomad4 AMR AF: 0.000262 AC: 0.000261917 AN: 0.000261917

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: 0.00228 AC: 0.00227847 AN: 0.00227847

Gnomad4 OTH AF: 0.000959 AC: 0.000958773 AN: 0.000958773

Alfa AF: 0.00155 Hom.: 2

Bravo AF: 0.00101

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00116 AC: 141

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

BDH1-related disorder Benign:1

Jul 14, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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	Pathogenic	0.76
BayesDel_addAF	Benign	0.0061	T
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	D;D;D;T
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	2.9	M;M;M;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.8	D;D;D;D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.71
MVP		1.0
MPC		0.99
ClinPred		0.22	T
GERP RS		5.8
Varity_R		0.71
gMVP		0.88
Mutation Taster		=89/11	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: rs144840608; hg19: chr3-197238857; COSMIC: COSV64017749; COSMIC: COSV64017749;