Genetic Variant MTX1:p.Ala119Thr (chr1-155209159-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002455.5(MTX1):c.355G>A(p.Ala119Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000333 in 1,503,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

MTX1
NM_002455.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.26

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008623689).

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.355G>A	p.Ala119Thr	missense	Exon 1 of 8	NP_002446.3
MTX1	NM_198883.3		c.355G>A	p.Ala119Thr	missense	Exon 1 of 7	NP_942584.2	Q13505-2
THBS3	NM_001407556.1		c.-289C>T		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.355G>A	p.Ala119Thr	missense	Exon 1 of 8	ENSP00000357360.3	Q13505-1
MTX1	ENST00000316721.8	TSL:1	c.355G>A	p.Ala119Thr	missense	Exon 1 of 7	ENSP00000317106.4	Q13505-2
MTX1	ENST00000609421.1	TSL:1	c.-93G>A		upstream_gene	N/A	ENSP00000476632.1	Q13505-3

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000473

AC:

AN:

105726

AF XY:

0.0000343

show subpopulations

Gnomad AFR exome

AF:

0.000770

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:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000207

AC:

AN:

1351070

Hom.:

Cov.:

AF XY:

0.0000166

AC XY:

AN XY:

662538

show subpopulations

African (AFR)

AF:

0.000717

AC:

AN:

29280

American (AMR)

AF:

0.00

AC:

AN:

27572

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22576

East Asian (EAS)

AF:

0.00

AC:

AN:

34708

South Asian (SAS)

AF:

0.00

AC:

AN:

74506

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46200

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4620

European-Non Finnish (NFE)

AF:

0.00000663

AC:

AN:

1055932

Other (OTH)

AF:

0.00

AC:

AN:

55676

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

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

AF:

0.000145

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.000531

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2092

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

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:

0.00

Hom.:

Bravo

AF:

0.000144

ExAC

AF:

0.0000345

AC:

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

0.083

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.95

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.017

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.49

M_CAP

Benign

0.033

MetaRNN

Benign

0.0086

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

-1.3

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.27

REVEL

Benign

0.0030

Sift

Benign

0.072

Sift4G

Benign

0.36

Polyphen

0.18

Vest4

0.067

MVP

0.29

MPC

0.24

ClinPred

0.015

GERP RS

-1.9

PromoterAI

-0.071

Neutral

(source)

Varity_R

0.021

gMVP

0.16

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over