2-206755068-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001039845.3(MDH1B):ā€‹c.851T>Gā€‹(p.Leu284Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,614,074 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.000062 ( 0 hom. )

Consequence

MDH1B
NM_001039845.3 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.11
Variant links:
Genes affected
MDH1B (HGNC:17836): (malate dehydrogenase 1B) Predicted to enable L-malate dehydrogenase activity. Predicted to be involved in NADH metabolic process; dicarboxylic acid metabolic process; and tricarboxylic acid cycle. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MDH1BNM_001039845.3 linkuse as main transcriptc.851T>G p.Leu284Arg missense_variant 5/12 ENST00000374412.8 NP_001034934.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MDH1BENST00000374412.8 linkuse as main transcriptc.851T>G p.Leu284Arg missense_variant 5/121 NM_001039845.3 ENSP00000363533 P4Q5I0G3-1

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152202
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.000132
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000438
AC:
11
AN:
251346
Hom.:
0
AF XY:
0.0000515
AC XY:
7
AN XY:
135842
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.0000968
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000622
AC:
91
AN:
1461872
Hom.:
0
Cov.:
31
AF XY:
0.0000660
AC XY:
48
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000782
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152202
Hom.:
0
Cov.:
32
AF XY:
0.0000807
AC XY:
6
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000132
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000118
Hom.:
1
Bravo
AF:
0.0000604
ExAC
AF:
0.0000247
AC:
3
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 GeneticsMay 09, 2022The c.851T>G (p.L284R) alteration is located in exon 5 (coding exon 5) of the MDH1B gene. This alteration results from a T to G substitution at nucleotide position 851, causing the leucine (L) at amino acid position 284 to be replaced by an arginine (R). 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
0.23
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.33
CADD
Benign
23
DANN
Benign
0.32
DEOGEN2
Benign
0.0082
T;.;.
Eigen
Benign
-0.30
Eigen_PC
Benign
-0.17
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Benign
0.79
T;T;T
M_CAP
Benign
0.010
T
MetaRNN
Uncertain
0.57
D;D;D
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.4
M;.;M
MutationTaster
Benign
1.0
D;N;N;N
PrimateAI
Benign
0.38
T
PROVEAN
Benign
0.77
N;N;N
REVEL
Benign
0.19
Sift
Benign
0.86
T;T;T
Sift4G
Benign
0.56
T;D;T
Polyphen
0.0040
B;.;B
Vest4
0.69
MutPred
0.63
Gain of MoRF binding (P = 0.0139);.;Gain of MoRF binding (P = 0.0139);
MVP
0.41
MPC
0.15
ClinPred
0.081
T
GERP RS
5.5
Varity_R
0.15
gMVP
0.69

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: rs149851373; hg19: chr2-207619792; API