Genetic Variant MTX1:p.Leu117Gln (chr1-155209154-T-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_001407556.1(THBS3):c.-284A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000088 in 1,363,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000088 ( 0 hom. )

Consequence

THBS3
NM_001407556.1 5_prime_UTR_premature_start_codon_gain

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=0.04104662).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407556.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MTX1	NM_002455.5	MANE Select	c.350T>A	p.Leu117Gln	missense	Exon 1 of 8	NP_002446.3
THBS3	NM_001407556.1		c.-284A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 23	NP_001394485.1
THBS3	NM_001407557.1		c.-382A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 24	NP_001394486.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTX1	ENST00000368376.8	TSL:1 MANE Select	c.350T>A	p.Leu117Gln	missense	Exon 1 of 8	ENSP00000357360.3	Q13505-1
MTX1	ENST00000316721.8	TSL:1	c.350T>A	p.Leu117Gln	missense	Exon 1 of 7	ENSP00000317106.4	Q13505-2
MTX1	ENST00000609421.1	TSL:1	c.-98T>A		upstream_gene	N/A	ENSP00000476632.1	Q13505-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000168

AC:

AN:

119070

AF XY:

0.00

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:

0.0000477

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000880

AC:

AN:

1363496

Hom.:

Cov.:

AF XY:

0.00000747

AC XY:

AN XY:

669230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29882

American (AMR)

AF:

0.00

AC:

AN:

30652

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23560

East Asian (EAS)

AF:

0.00

AC:

AN:

34858

South Asian (SAS)

AF:

0.00

AC:

AN:

76398

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46696

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4690

European-Non Finnish (NFE)

AF:

0.0000113

AC:

AN:

1060548

Other (OTH)

AF:

0.00

AC:

AN:

56212

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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.:

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

0.053

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.016

(source)

DANN

Benign

0.49

DEOGEN2

Benign

0.022

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.3

FATHMM_MKL

Benign

0.0040

LIST_S2

Benign

0.39

M_CAP

Benign

0.011

MetaRNN

Benign

0.041

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

-4.2

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.22

REVEL

Benign

0.0090

Sift

Benign

0.34

Sift4G

Benign

0.41

Polyphen

0.0

Vest4

0.042

MutPred

0.31

Gain of MoRF binding (P = 0.0752)

MVP

0.048

MPC

0.25

ClinPred

0.32

GERP RS

-8.4

PromoterAI

-0.019

Neutral

(source)

Varity_R

0.048

gMVP

0.12

Mutation Taster

=94/6

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over