2-206750979-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001039845.3(MDH1B):​c.1007G>T​(p.Gly336Val) variant causes a missense change. The variant allele was found at a frequency of 0.000023 in 1,611,676 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 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

MDH1B
NM_001039845.3 missense

Scores

8
8
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.14
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 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.755

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MDH1BNM_001039845.3 linkuse as main transcriptc.1007G>T p.Gly336Val missense_variant 6/12 ENST00000374412.8 NP_001034934.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MDH1BENST00000374412.8 linkuse as main transcriptc.1007G>T p.Gly336Val missense_variant 6/121 NM_001039845.3 ENSP00000363533 P4Q5I0G3-1

Frequencies

GnomAD3 genomes
AF:
0.000164
AC:
25
AN:
152128
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000338
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000654
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:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
250532
Hom.:
0
AF XY:
0.0000369
AC XY:
5
AN XY:
135402
show subpopulations
Gnomad AFR exome
AF:
0.000246
Gnomad AMR exome
AF:
0.0000583
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000822
AC:
12
AN:
1459430
Hom.:
0
Cov.:
30
AF XY:
0.00000826
AC XY:
6
AN XY:
725956
show subpopulations
Gnomad4 AFR exome
AF:
0.0000599
Gnomad4 AMR exome
AF:
0.000135
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:
0.00000180
Gnomad4 OTH exome
AF:
0.0000332
GnomAD4 genome
AF:
0.000164
AC:
25
AN:
152246
Hom.:
0
Cov.:
32
AF XY:
0.000175
AC XY:
13
AN XY:
74444
show subpopulations
Gnomad4 AFR
AF:
0.000337
Gnomad4 AMR
AF:
0.000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.0000772
Hom.:
0
Bravo
AF:
0.000238
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000247
AC:
3

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 GeneticsJan 23, 2024The c.1007G>T (p.G336V) alteration is located in exon 6 (coding exon 6) of the MDH1B gene. This alteration results from a G to T substitution at nucleotide position 1007, causing the glycine (G) at amino acid position 336 to be replaced by a valine (V). 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
Pathogenic
0.72
BayesDel_addAF
Uncertain
0.023
T
BayesDel_noAF
Uncertain
0.090
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.34
T;.;.
Eigen
Pathogenic
0.87
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.86
D;D;D
M_CAP
Uncertain
0.097
D
MetaRNN
Pathogenic
0.75
D;D;D
MetaSVM
Benign
-1.1
T
MutationAssessor
Pathogenic
3.0
M;.;M
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.53
T
PROVEAN
Pathogenic
-7.0
D;D;D
REVEL
Uncertain
0.42
Sift
Uncertain
0.0030
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;.;D
Vest4
0.93
MVP
0.48
MPC
0.58
ClinPred
0.95
D
GERP RS
6.0
Varity_R
0.88
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.32
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.32
Position offset: -45

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: rs373097195; hg19: chr2-207615703; API