Genetic Variant MTCH2:p.Pro290Thr (chr11-47618877-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_014342.4(MTCH2):c.868C>A(p.Pro290Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000589 in 1,358,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 16)

Exomes 𝑓: 0.0000059 ( 0 hom. )

Consequence

MTCH2
NM_014342.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.23

Publications

61 publications found

Variant links:

Genes affected

MTCH2 (HGNC:17587): (mitochondrial carrier 2) This gene encodes a member of the SLC25 family of nuclear-encoded transporters that are localized in the inner mitochondrial membrane. Members of this superfamily are involved in many metabolic pathways and cell functions. Genome-wide association studies in human have identified single-nucleotide polymorphisms in several loci associated with obesity. This gene is one such locus, which is highly expressed in white adipose tissue and adipocytes, and thought to play a regulatory role in adipocyte differentiation and biology. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. A recent study showed this gene to be an authentic stop codon readthrough target that can produce two isoforms from the same mRNA by use of alternative in-frame translation termination codons. [provided by RefSeq, Dec 2017]

MTCH2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.846

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTCH2	NM_014342.4 link	c.868C>A	p.Pro290Thr	missense_variant	Exon 13 of 13	ENST00000302503.8	NP_055157.1	Q9Y6C9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTCH2	ENST00000302503.8 link	c.868C>A	p.Pro290Thr	missense_variant	Exon 13 of 13	1	NM_014342.4	ENSP00000303222.3		Q9Y6C9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000802

AC:

AN:

249444

AF XY:

0.00000740

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:

0.00000889

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000589

AC:

AN:

1358874

Hom.:

Cov.:

AF XY:

0.00000750

AC XY:

AN XY:

666624

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29622

American (AMR)

AF:

0.00

AC:

AN:

38486

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23378

East Asian (EAS)

AF:

0.00

AC:

AN:

36318

South Asian (SAS)

AF:

0.0000150

AC:

AN:

66848

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42312

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4944

European-Non Finnish (NFE)

AF:

0.00000660

AC:

AN:

1060788

Other (OTH)

AF:

0.00

AC:

AN:

56178

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

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:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0035

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.97

M_CAP

Uncertain

0.087

MetaRNN

Pathogenic

0.85

MetaSVM

Uncertain

0.38

MutationAssessor

Benign

1.9

PhyloP100

6.2

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.56

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.016

Polyphen

1.0

Vest4

0.61

MutPred

0.54

Gain of phosphorylation at P290 (P = 0.0304);

MVP

0.92

MPC

0.72

ClinPred

0.75

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.82

Mutation Taster

=51/49

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over