Genetic Variant MDH1B:p.Ala360Thr (chr2-206749158-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001039845.3(MDH1B):c.1078G>A(p.Ala360Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A360S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MDH1B
NM_001039845.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.10

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10606909).

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.1078G>A	p.Ala360Thr	missense	Exon 7 of 12	NP_001034934.1	Q5I0G3-1
MDH1B	NM_001282940.2		c.1078G>A	p.Ala360Thr	missense	Exon 7 of 12	NP_001269869.1	Q5I0G3-2
MDH1B	NM_001330223.2		c.784G>A	p.Ala262Thr	missense	Exon 6 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.1078G>A	p.Ala360Thr	missense	Exon 7 of 12	ENSP00000363533.3	Q5I0G3-1
MDH1B	ENST00000432911.5	TSL:1	n.439G>A		non_coding_transcript_exon	Exon 5 of 10	ENSP00000392464.1	Q5I0G3-3
MDH1B	ENST00000454776.6	TSL:2	c.1078G>A	p.Ala360Thr	missense	Exon 7 of 12	ENSP00000389916.2	Q5I0G3-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251074

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461724

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111930

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.73

(source)

DANN

Benign

0.48

DEOGEN2

Benign

0.011

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.56

M_CAP

Benign

0.028

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.69

PhyloP100

-2.1

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.070

REVEL

Benign

0.080

Sift

Benign

0.59

Sift4G

Benign

0.58

Polyphen

0.0050

Vest4

0.099

MutPred

0.67

Gain of ubiquitination at K355 (P = 0.1245)

MVP

0.25

MPC

0.10

ClinPred

0.028

GERP RS

-6.6

Varity_R

0.027

gMVP

0.40

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over