chr2-63597394-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_005917.4(MDH1):c.200-5C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000259 in 1,384,644 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00025 ( 2 hom. )

Consequence

MDH1
NM_005917.4 splice_region, intron

Scores

Splicing: ADA: 0.01130

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0580

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

Bardet-Biedl syndrome 15
Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Bardet-Biedl syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
heart defect - tongue hamartoma - polysyndactyly syndrome
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

WDPCP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.22).

BP6

Variant 2-63597394-C-A is Benign according to our data. Variant chr2-63597394-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1694958.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 2 Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005917.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MDH1	NM_005917.4	MANE Select	c.200-5C>A	splice_region intron	N/A	NP_005908.1	P40925-1
MDH1	NM_001316374.2		c.200-5C>A	splice_region intron	N/A	NP_001303303.1	A0A5K1VW95
MDH1	NM_001199111.2		c.254-5C>A	splice_region intron	N/A	NP_001186040.1	P40925-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MDH1	ENST00000233114.13	TSL:1 MANE Select	c.200-5C>A		splice_region intron	N/A	ENSP00000233114.8	P40925-1
MDH1	ENST00000472098.5	TSL:1	n.149-5C>A		splice_region intron	N/A
MDH1	ENST00000906787.1		c.126C>A	p.Ser42Ser	synonymous	Exon 3 of 8	ENSP00000576846.1

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00848

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000352

AC:

AN:

153608

AF XY:

0.000367

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00557

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000336

GnomAD4 exome

AF:

0.000254

AC:

313

AN:

1232390

Hom.:

Cov.:

AF XY:

0.000234

AC XY:

140

AN XY:

599140

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25950

American (AMR)

AF:

0.00

AC:

AN:

20044

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18580

East Asian (EAS)

AF:

0.00949

AC:

303

AN:

31916

South Asian (SAS)

AF:

0.0000216

AC:

AN:

46380

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45814

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4908

European-Non Finnish (NFE)

AF:

0.00000101

AC:

AN:

989434

Other (OTH)

AF:

0.000162

AC:

AN:

49364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000302

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41558

American (AMR)

AF:

0.0000654

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00850

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68010

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000357

Hom.:

Bravo

AF:

0.000283

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

0.058

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.011

dbscSNV1_RF

Benign

0.092

SpliceAI score (max)

0.19

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over