Genetic Variant MDH1B:p.Glu489Asp (chr2-206739654-C-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_001039845.3(MDH1B):c.1467G>C(p.Glu489Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 1,613,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

MDH1B
NM_001039845.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.489

Publications

2 publications found

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]

MDH1B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0111659765).

BP6

Variant 2-206739654-C-G is Benign according to our data. Variant chr2-206739654-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3394034.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039845.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MDH1B	NM_001039845.3	MANE Select	c.1467G>C	p.Glu489Asp	missense	Exon 11 of 12	NP_001034934.1	Q5I0G3-1
MDH1B	NM_001282940.2		c.1464G>C	p.Glu488Asp	missense	Exon 11 of 12	NP_001269869.1	Q5I0G3-2
MDH1B	NM_001330223.2		c.1173G>C	p.Glu391Asp	missense	Exon 10 of 11	NP_001317152.1	C9JER5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MDH1B	ENST00000374412.8	TSL:1 MANE Select	c.1467G>C	p.Glu489Asp	missense	Exon 11 of 12	ENSP00000363533.3	Q5I0G3-1
MDH1B	ENST00000432911.5	TSL:1	n.*254G>C		non_coding_transcript_exon	Exon 9 of 10	ENSP00000392464.1	Q5I0G3-3
MDH1B	ENST00000432911.5	TSL:1	n.*254G>C		3_prime_UTR	Exon 9 of 10	ENSP00000392464.1	Q5I0G3-3

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000892

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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:

0.0000876

AC:

AN:

251002

AF XY:

0.0000663

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461544

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727072

show subpopulations

African (AFR)

AF:

0.000777

AC:

AN:

33466

American (AMR)

AF:

0.0000224

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00

AC:

AN:

86192

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111834

Other (OTH)

AF:

0.00

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.428

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:

0.000295

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00103

AC:

AN:

41584

American (AMR)

AF:

0.00

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.0000223

Hom.:

Bravo

AF:

0.000283

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000989

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.059

(source)

DANN

Benign

0.088

DEOGEN2

Benign

0.0047

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.22

M_CAP

Benign

0.0026

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.55

PhyloP100

-0.49

PrimateAI

Benign

0.35

PROVEAN

Benign

0.070

REVEL

Benign

0.010

Sift

Benign

0.64

Sift4G

Benign

0.52

Polyphen

0.0

Vest4

0.040

MutPred

0.075

Loss of helix (P = 0.0558)

MVP

0.081

MPC

0.092

ClinPred

0.0063

GERP RS

-5.8

Varity_R

0.035

gMVP

0.13

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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