Variant chr2-63597539-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_005917.4(MDH1):c.340G>A(p.Ala114Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000753 in 1,328,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

MDH1
NM_005917.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.27

Variant links:

Genes affected

MDH1 (HGNC:6970): (malate dehydrogenase 1) This gene encodes an enzyme that catalyzes the NAD/NADH-dependent, reversible oxidation of malate to oxaloacetate in many metabolic pathways, including the citric acid cycle. Two main isozymes are known to exist in eukaryotic cells: one is found in the mitochondrial matrix and the other in the cytoplasm. This gene encodes the cytosolic isozyme, which plays a key role in the malate-aspartate shuttle that allows malate to pass through the mitochondrial membrane to be transformed into oxaloacetate for further cellular processes. Alternatively spliced transcript variants have been found for this gene. A recent study showed that a C-terminally extended isoform is produced by use of an alternative in-frame translation termination codon via a stop codon readthrough mechanism, and that this isoform is localized in the peroxisomes. Pseudogenes have been identified on chromosomes X and 6. [provided by RefSeq, Feb 2016]

MDH1 links:

WDPCP (HGNC:28027): (WD repeat containing planar cell polarity effector) This gene encodes a cytoplasmic WD40 repeat protein. A similar gene in frogs encodes a planar cell polarity protein that plays a critical role in collective cell movement and ciliogenesis by mediating septin localization. Mutations in this gene are associated with Bardet-Biedl syndrome 15 and may also play a role in Meckel-Gruber syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

WDPCP links:

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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	UniProt
MDH1	NM_005917.4 linkuse as main transcript	c.340G>A	p.Ala114Thr	missense_variant	4/9	ENST00000233114.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MDH1	ENST00000233114.13 linkuse as main transcript	c.340G>A	p.Ala114Thr	missense_variant	4/9	1	NM_005917.4	P1	P40925-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.53e-7

AC:

AN:

1328062

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

653772

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:

0.00

Gnomad4 NFE exome

AF:

9.64e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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 submitter

clinical testing

Ambry Genetics

Nov 08, 2022

The c.394G>A (p.A132T) alteration is located in exon 4 (coding exon 4) of the MDH1 gene. This alteration results from a G to A substitution at nucleotide position 394, causing the alanine (A) at amino acid position 132 to be replaced by a threonine (T). 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

0.085

BayesDel_addAF

Benign

-0.032

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Uncertain

0.43

T;T;T;.;.

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.86

D;D;D;D;D

M_CAP

Benign

0.054

MetaRNN

Benign

0.25

T;T;T;T;T

MetaSVM

Uncertain

-0.25

MutationAssessor

Uncertain

2.3

M;.;.;.;.

MutationTaster

Benign

0.87

D;D;D;D;D;D

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.60

N;N;N;N;N

REVEL

Benign

0.21

Sift

Benign

0.12

T;T;T;T;T

Sift4G

Uncertain

0.042

D;T;D;D;D

Polyphen

0.0

B;.;.;.;.

Vest4

0.26

MutPred

0.41

Loss of catalytic residue at A114 (P = 0.084);.;.;.;.;

MVP

0.72

MPC

0.29

ClinPred

0.38

GERP RS

0.94

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.026

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.30

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.30

Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over