2-63597407-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_005917.4(MDH1):c.208G>A(p.Ala70Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000398 in 1,427,172 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (13 hom.)
• Consequence: MDH1 NM_005917.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.53

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]

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010978013).
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MDH1	NM_005917.4	c.208G>A	p.Ala70Thr	missense_variant	4/9	ENST00000233114.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MDH1	ENST00000233114.13	c.208G>A	p.Ala70Thr	missense_variant	4/9	1	NM_005917.4	P1

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00953

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000855 AC: 144 AN: 168414 Hom.: 4 AF XY: 0.00106 AC XY: 98 AN XY: 92670

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: 0.00849

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000116

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000409 AC: 522 AN: 1274884 Hom.: 13 Cov.: 30 AF XY: 0.000578 AC XY: 360 AN XY: 623174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000302

Gnomad4 SAS exome AF: 0.00837

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000890

Gnomad4 OTH exome AF: 0.000740

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152288 Hom.: 0 Cov.: 33 AF XY: 0.000510 AC XY: 38 AN XY: 74458

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00933

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000832 Hom.: 1

Bravo AF: 0.0000831

ExAC AF: 0.00116 AC: 141

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;T;.;T;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T;T;T;T;T
MetaRNN	Benign	0.011	T;T;T;T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	2.0	M;.;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.1	N;N;N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.23	T;D;T;T;T
Sift4G	Benign	0.28	T;T;T;T;T
Polyphen		0.85	P;.;.;.;.
Vest4		0.27
MutPred		0.46		Loss of ubiquitination at K66 (P = 0.0524);.;.;.;.;
MVP		0.79
MPC		0.36
ClinPred		0.12	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.032
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs533261577; hg19: chr2-63824541; COSMIC: COSV51865488; COSMIC: COSV51865488;