dbSNP rs144065455: MTREX:p.Gly666Arg (chr5-55379139-G-A) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_015360.5(MTREX):c.1996G>A(p.Gly666Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000231 in 1,608,672 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 1 hom. )

Consequence

MTREX
NM_015360.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.90

Publications

4 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.27792257).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTREX	NM_015360.5 link	c.1996G>A	p.Gly666Arg	missense_variant	Exon 18 of 27	ENST00000230640.10	NP_056175.3	P42285Q3MHC9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MTREX	ENST00000230640.10 link	c.1996G>A	p.Gly666Arg	missense_variant	Exon 18 of 27	1	NM_015360.5	ENSP00000230640.5	P42285
MTREX	ENST00000506750.5 link	n.*1521G>A		non_coding_transcript_exon_variant	Exon 16 of 25	2		ENSP00000425042.1	D6REC7
MTREX	ENST00000506750.5 link	n.*1521G>A		3_prime_UTR_variant	Exon 16 of 25	2		ENSP00000425042.1	D6REC7

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000329

AC:

AN:

248892

AF XY:

0.000349

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000406

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000635

Gnomad NFE exome

AF:

0.000371

Gnomad OTH exome

AF:

0.000493

GnomAD4 exome

AF:

0.000239

AC:

348

AN:

1456500

Hom.:

Cov.:

AF XY:

0.000257

AC XY:

186

AN XY:

724912

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33382

American (AMR)

AF:

0.000358

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26078

East Asian (EAS)

AF:

0.00

AC:

AN:

39530

South Asian (SAS)

AF:

0.000418

AC:

AN:

86134

European-Finnish (FIN)

AF:

0.000675

AC:

AN:

51830

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.000219

AC:

243

AN:

1108866

Other (OTH)

AF:

0.000199

AC:

AN:

60240

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000151

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41438

American (AMR)

AF:

0.000393

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.000255

Hom.:

Bravo

AF:

0.000174

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000396

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 09, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1996G>A (p.G666R) alteration is located in exon 18 (coding exon 18) of the SKIV2L2 gene. This alteration results from a G to A substitution at nucleotide position 1996, causing the glycine (G) at amino acid position 666 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.090

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.0086

MetaRNN

Benign

0.28

MetaSVM

Benign

-0.97

PhyloP100

5.9

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.2

REVEL

Benign

0.10

Sift

Benign

0.054

Sift4G

Benign

0.33

Polyphen

0.37

Vest4

0.71

MutPred

0.37

Gain of sheet (P = 0.0266);

MVP

0.56

MPC

0.36

ClinPred

0.043

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.23

gMVP

0.33

Mutation Taster

=87/13

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over