dbSNP rs964880: MDH1:c.498+506C>A (chr2-63599798-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005917.4(MDH1):c.498+506C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.803 in 152,176 control chromosomes in the GnomAD database, including 49,759 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.80 ( 49741 hom., cov: 32)

Exomes 𝑓: 0.73 ( 18 hom. )

Consequence

MDH1
NM_005917.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.383

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.02).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.959 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDH1	NM_005917.4 link	c.498+506C>A		intron_variant	Intron 5 of 8	ENST00000233114.13	NP_005908.1	P40925-1V9HWF2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDH1	ENST00000233114.13 link	c.498+506C>A		intron_variant	Intron 5 of 8	1	NM_005917.4	ENSP00000233114.8		P40925-1

Frequencies

GnomAD3 genomes

AF:

0.803

AC:

122067

AN:

151998

Hom.:

49671

Cov.:

show subpopulations

Gnomad AFR

AF:

0.922

Gnomad AMI

AF:

0.838

Gnomad AMR

AF:

0.824

Gnomad ASJ

AF:

0.795

Gnomad EAS

AF:

0.982

Gnomad SAS

AF:

0.834

Gnomad FIN

AF:

0.779

Gnomad MID

AF:

0.759

Gnomad NFE

AF:

0.715

Gnomad OTH

AF:

0.767

GnomAD4 exome

AF:

0.733

AC:

AN:

Hom.:

Cov.:

AF XY:

0.788

AC XY:

AN XY:

show subpopulations

Gnomad4 EAS exome

AF:

0.833

Gnomad4 NFE exome

AF:

0.740

Gnomad4 OTH exome

AF:

0.500

GnomAD4 genome

AF:

0.803

AC:

122201

AN:

152116

Hom.:

49741

Cov.:

AF XY:

0.807

AC XY:

59999

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.922

Gnomad4 AMR

AF:

0.824

Gnomad4 ASJ

AF:

0.795

Gnomad4 EAS

AF:

0.982

Gnomad4 SAS

AF:

0.835

Gnomad4 FIN

AF:

0.779

Gnomad4 NFE

AF:

0.715

Gnomad4 OTH

AF:

0.770

Alfa

AF:

0.747

Hom.:

5328

Bravo

AF:

0.810

Asia WGS

AF:

0.902

AC:

3138

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.65

DANN

Benign

0.28

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over