2-206755216-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001039845.3(MDH1B):​c.703C>T​(p.Leu235Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

MDH1B
NM_001039845.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.478
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.13265651).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MDH1BNM_001039845.3 linkuse as main transcriptc.703C>T p.Leu235Phe 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.703C>T p.Leu235Phe missense_variant 5/121 NM_001039845.3 ENSP00000363533 P4Q5I0G3-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152200
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000441
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000557
AC:
14
AN:
251266
Hom.:
0
AF XY:
0.0000442
AC XY:
6
AN XY:
135792
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000229
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000335
AC:
49
AN:
1461870
Hom.:
0
Cov.:
31
AF XY:
0.0000385
AC XY:
28
AN XY:
727234
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000134
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000325
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000809
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152200
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74342
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000441
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000165
Hom.:
0
Bravo
AF:
0.0000340
ExAC
AF:
0.0000741
AC:
9

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 16, 2021The c.703C>T (p.L235F) alteration is located in exon 5 (coding exon 5) of the MDH1B gene. This alteration results from a C to T substitution at nucleotide position 703, causing the leucine (L) at amino acid position 235 to be replaced by a phenylalanine (F). 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
0.10
BayesDel_addAF
Benign
-0.41
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
10
DANN
Benign
0.88
DEOGEN2
Benign
0.031
T;.;.
Eigen
Benign
-0.48
Eigen_PC
Benign
-0.47
FATHMM_MKL
Benign
0.15
N
LIST_S2
Benign
0.77
T;T;T
M_CAP
Benign
0.0088
T
MetaRNN
Benign
0.13
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.4
M;.;M
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-0.77
N;N;N
REVEL
Benign
0.13
Sift
Benign
0.41
T;T;T
Sift4G
Benign
0.63
T;T;T
Polyphen
0.0060
B;.;B
Vest4
0.17
MutPred
0.59
Loss of catalytic residue at L235 (P = 0.1648);.;Loss of catalytic residue at L235 (P = 0.1648);
MVP
0.27
MPC
0.12
ClinPred
0.089
T
GERP RS
4.7
Varity_R
0.088
gMVP
0.40

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: rs141930630; hg19: chr2-207619940; API