Genetic Variant MTREX:p.Pro37Thr (chr5-55308122-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015360.5(MTREX):c.109C>A(p.Pro37Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P37L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MTREX
NM_015360.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.229

Publications

0 publications found

Variant links:

Genes affected

MTREX (HGNC:18734): (Mtr4 exosome RNA helicase) Enables ATP binding activity and RNA helicase activity. Involved in RNA catabolic process; cellular response to DNA damage stimulus; and maturation of 5.8S rRNA. Located in nucleoplasm. Part of TRAMP complex and catalytic step 2 spliceosome. Colocalizes with nuclear exosome (RNase complex). Biomarker of amyotrophic lateral sclerosis. [provided by Alliance of Genome Resources, Apr 2022]

MTREX links:

ENSG00000298331 (HGNC:):

ENSG00000298331 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.058398843).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015360.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTREX	NM_015360.5	MANE Select	c.109C>A	p.Pro37Thr	missense	Exon 1 of 27	NP_056175.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTREX	ENST00000230640.10	TSL:1 MANE Select	c.109C>A	p.Pro37Thr	missense	Exon 1 of 27	ENSP00000230640.5	P42285
MTREX	ENST00000929144.1		c.109C>A	p.Pro37Thr	missense	Exon 1 of 28	ENSP00000599203.1
MTREX	ENST00000929142.1		c.109C>A	p.Pro37Thr	missense	Exon 1 of 29	ENSP00000599201.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1458838

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725510

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33302

American (AMR)

AF:

0.00

AC:

AN:

44254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25966

East Asian (EAS)

AF:

0.00

AC:

AN:

39502

South Asian (SAS)

AF:

0.00

AC:

AN:

86082

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1110344

Other (OTH)

AF:

0.00

AC:

AN:

60264

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

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.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

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

0.055

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.070

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.63

M_CAP

Benign

0.0039

MetaRNN

Benign

0.058

MetaSVM

Benign

-1.0

PhyloP100

0.23

PrimateAI

Benign

0.32

PROVEAN

Benign

0.33

REVEL

Benign

0.059

Sift

Benign

0.29

Sift4G

Benign

0.50

Polyphen

0.0

Vest4

0.17

MutPred

0.28

Loss of catalytic residue at P37 (P = 5e-04)

MVP

0.27

MPC

0.56

ClinPred

0.087

GERP RS

1.2

PromoterAI

-0.045

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.075

gMVP

0.14

Mutation Taster

=99/1

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

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