3-197514299-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_203314.3(BDH1):​c.527C>T​(p.Thr176Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 1,613,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

BDH1
NM_203314.3 missense

Scores

9
7
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.80
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.947

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BDH1NM_203314.3 linkuse as main transcriptc.527C>T p.Thr176Met missense_variant 7/8 ENST00000392379.6 NP_976059.1 Q02338A0A384MTY4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BDH1ENST00000392379.6 linkuse as main transcriptc.527C>T p.Thr176Met missense_variant 7/85 NM_203314.3 ENSP00000376184.1 Q02338

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152136
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000797
AC:
20
AN:
251058
Hom.:
0
AF XY:
0.0000811
AC XY:
11
AN XY:
135668
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000319
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000793
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000472
AC:
69
AN:
1461474
Hom.:
0
Cov.:
30
AF XY:
0.0000481
AC XY:
35
AN XY:
727014
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000291
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000441
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152136
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74302
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000416
ExAC
AF:
0.0000659
AC:
8
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 20, 2023The c.527C>T (p.T176M) alteration is located in exon 7 (coding exon 5) of the BDH1 gene. This alteration results from a C to T substitution at nucleotide position 527, causing the threonine (T) at amino acid position 176 to be replaced by a methionine (M). 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
0.33
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Pathogenic
0.37
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.82
D;D;D;D;.;D;D
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Pathogenic
0.97
D
M_CAP
Uncertain
0.10
D
MetaRNN
Pathogenic
0.95
D;D;D;D;D;D;D
MetaSVM
Uncertain
0.78
D
MutationAssessor
Uncertain
2.6
M;M;M;.;.;.;.
PrimateAI
Uncertain
0.62
T
PROVEAN
Pathogenic
-5.6
D;D;D;D;D;D;D
REVEL
Pathogenic
0.70
Sift
Pathogenic
0.0
D;D;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;.;.
Polyphen
1.0
D;D;D;.;.;.;.
Vest4
0.97
MutPred
0.77
Gain of MoRF binding (P = 0.0939);Gain of MoRF binding (P = 0.0939);Gain of MoRF binding (P = 0.0939);.;.;.;Gain of MoRF binding (P = 0.0939);
MVP
0.98
MPC
0.90
ClinPred
0.91
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.63
gMVP
0.87

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs746191768; hg19: chr3-197241170; API