2-206749158-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001039845.3(MDH1B):​c.1078G>T​(p.Ala360Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000688 in 1,613,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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: 33)
Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

MDH1B
NM_001039845.3 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.10
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 Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06038952).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MDH1BNM_001039845.3 linkuse as main transcriptc.1078G>T p.Ala360Ser missense_variant 7/12 ENST00000374412.8 NP_001034934.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MDH1BENST00000374412.8 linkuse as main transcriptc.1078G>T p.Ala360Ser missense_variant 7/121 NM_001039845.3 ENSP00000363533 P4Q5I0G3-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152086
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000242
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:
0.00
GnomAD3 exomes
AF:
0.0000757
AC:
19
AN:
251074
Hom.:
0
AF XY:
0.0000811
AC XY:
11
AN XY:
135696
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:
0.000167
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000732
AC:
107
AN:
1461724
Hom.:
0
Cov.:
31
AF XY:
0.0000646
AC XY:
47
AN XY:
727134
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000935
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152086
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74288
show subpopulations
Gnomad4 AFR
AF:
0.0000242
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:
0.00
Alfa
AF:
0.0000595
Hom.:
0
Bravo
AF:
0.0000416
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000173
AC:
21
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 GeneticsFeb 28, 2023The c.1078G>T (p.A360S) alteration is located in exon 7 (coding exon 7) of the MDH1B gene. This alteration results from a G to T substitution at nucleotide position 1078, causing the alanine (A) at amino acid position 360 to be replaced by a serine (S). 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
0.082
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.61
CADD
Benign
0.043
DANN
Benign
0.23
DEOGEN2
Benign
0.011
T;.;.
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.016
N
LIST_S2
Benign
0.54
T;T;T
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.060
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.33
N;.;N
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.22
T
PROVEAN
Benign
0.63
N;N;N
REVEL
Benign
0.084
Sift
Benign
0.73
T;T;T
Sift4G
Benign
0.85
T;T;T
Polyphen
0.014
B;.;B
Vest4
0.10
MVP
0.32
MPC
0.094
ClinPred
0.035
T
GERP RS
-6.6
Varity_R
0.035
gMVP
0.40

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs143034331; hg19: chr2-207613882; API