Genetic Variant MTX1:p.Leu117Arg (chr1-155209154-T-G) – 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_002455.5(MTX1):c.350T>G(p.Leu117Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 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. L117P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

MTX1
NM_002455.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.16

Publications

1 publications found

Variant links:

Genes affected

MTX1 (HGNC:7504): (metaxin 1) Predicted to be involved in mitochondrion organization. Part of MIB complex and SAM complex. [provided by Alliance of Genome Resources, Apr 2022]

MTX1 links:

THBS3 (HGNC:11787): (thrombospondin 3) The protein encoded by this gene belongs to the thrombospondin family. Thrombospondin family members are adhesive glycoproteins that mediate cell-to-cell and cell-to-matrix interactions. This protein forms a pentameric molecule linked by a single disulfide bond. This gene shares a common promoter with metaxin 1. Alternate splicing results in coding and non-coding transcript variants. [provided by RefSeq, Nov 2011]

THBS3 Gene-Disease associations (from GenCC):

Tourette syndrome
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

THBS3 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=0.036872238).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002455.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTX1	NM_002455.5	MANE Select	c.350T>G	p.Leu117Arg	missense	Exon 1 of 8	NP_002446.3
MTX1	NM_198883.3		c.350T>G	p.Leu117Arg	missense	Exon 1 of 7	NP_942584.2	Q13505-2
THBS3	NM_001407556.1		c.-284A>C		5_prime_UTR	Exon 1 of 23	NP_001394485.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTX1	ENST00000368376.8	TSL:1 MANE Select	c.350T>G	p.Leu117Arg	missense	Exon 1 of 8	ENSP00000357360.3	Q13505-1
MTX1	ENST00000316721.8	TSL:1	c.350T>G	p.Leu117Arg	missense	Exon 1 of 7	ENSP00000317106.4	Q13505-2
MTX1	ENST00000609421.1	TSL:1	c.-98T>G		upstream_gene	N/A	ENSP00000476632.1	Q13505-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.0060

(source)

DANN

Benign

0.43

DEOGEN2

Benign

0.019

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.4

FATHMM_MKL

Benign

0.0016

LIST_S2

Benign

0.40

M_CAP

Benign

0.011

MetaRNN

Benign

0.037

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

PhyloP100

-4.2

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.28

REVEL

Benign

0.011

Sift

Benign

0.86

Sift4G

Benign

0.79

Polyphen

0.0

Vest4

0.030

MutPred

0.39

Gain of MoRF binding (P = 0.007)

MVP

0.048

MPC

0.34

ClinPred

0.15

GERP RS

-8.4

PromoterAI

0.0064

Neutral

(source)

Varity_R

0.060

gMVP

0.098

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over