2-206751028-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001039845.3(MDH1B):​c.958G>T​(p.Val320Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000577 in 1,608,208 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00040 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00060 ( 1 hom. )

Consequence

MDH1B
NM_001039845.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.267
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.

BP4
Computational evidence support a benign effect (MetaRNN=0.087547034).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MDH1BNM_001039845.3 linkuse as main transcriptc.958G>T p.Val320Phe 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.958G>T p.Val320Phe missense_variant 6/121 NM_001039845.3 ENSP00000363533 P4Q5I0G3-1

Frequencies

GnomAD3 genomes
AF:
0.000401
AC:
61
AN:
152076
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000393
Gnomad ASJ
AF:
0.00289
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000544
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000384
AC:
96
AN:
250200
Hom.:
0
AF XY:
0.000333
AC XY:
45
AN XY:
135196
show subpopulations
Gnomad AFR exome
AF:
0.000370
Gnomad AMR exome
AF:
0.000351
Gnomad ASJ exome
AF:
0.00159
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000529
Gnomad OTH exome
AF:
0.000328
GnomAD4 exome
AF:
0.000595
AC:
867
AN:
1456014
Hom.:
1
Cov.:
29
AF XY:
0.000577
AC XY:
418
AN XY:
724342
show subpopulations
Gnomad4 AFR exome
AF:
0.000120
Gnomad4 AMR exome
AF:
0.000359
Gnomad4 ASJ exome
AF:
0.00211
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000117
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000683
Gnomad4 OTH exome
AF:
0.000566
GnomAD4 genome
AF:
0.000401
AC:
61
AN:
152194
Hom.:
1
Cov.:
32
AF XY:
0.000309
AC XY:
23
AN XY:
74392
show subpopulations
Gnomad4 AFR
AF:
0.000168
Gnomad4 AMR
AF:
0.000393
Gnomad4 ASJ
AF:
0.00289
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000544
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000618
Hom.:
0
Bravo
AF:
0.000495
TwinsUK
AF:
0.00135
AC:
5
ALSPAC
AF:
0.00104
AC:
4
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000930
AC:
8
ExAC
AF:
0.000371
AC:
45

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 GeneticsSep 07, 2022The c.958G>T (p.V320F) 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 958, causing the valine (V) at amino acid position 320 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
0.34
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.29
CADD
Benign
12
DANN
Uncertain
0.99
DEOGEN2
Benign
0.21
T;.;.
Eigen
Benign
-0.84
Eigen_PC
Benign
-0.90
FATHMM_MKL
Benign
0.12
N
LIST_S2
Benign
0.82
T;T;T
M_CAP
Benign
0.076
D
MetaRNN
Benign
0.088
T;T;T
MetaSVM
Benign
-0.83
T
MutationAssessor
Benign
1.9
M;.;M
MutationTaster
Benign
1.0
D;N;N;N
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-2.3
N;N;N
REVEL
Benign
0.27
Sift
Benign
0.11
T;T;T
Sift4G
Benign
0.20
T;D;T
Polyphen
0.22
B;.;B
Vest4
0.79
MVP
0.29
MPC
0.26
ClinPred
0.019
T
GERP RS
-2.7
Varity_R
0.11
gMVP
0.92

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
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: rs148716417; hg19: chr2-207615752; API