1-155209232-C-G

Variant names:

• chr1-155209232-C-G
• rs746148105
• NM_002455.5:c.428C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002455.5(MTX1):​c.428C>G​(p.Pro143Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000769 in 1,299,568 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P143L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: MTX1 NM_002455.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.79
• Publications: 0 publications found

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]

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30477965).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTX1	NM_002455.5	MANE Select	c.428C>G	p.Pro143Arg	missense	Exon 1 of 8	NP_002446.3
	MTX1	NM_198883.3		c.428C>G	p.Pro143Arg	missense	Exon 1 of 7	NP_942584.2	Q13505-2
	THBS3	NM_001407556.1		c.-362G>C		upstream_gene	N/A	NP_001394485.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTX1	ENST00000368376.8	TSL:1 MANE Select	c.428C>G	p.Pro143Arg	missense	Exon 1 of 8	ENSP00000357360.3	Q13505-1
	MTX1	ENST00000316721.8	TSL:1	c.428C>G	p.Pro143Arg	missense	Exon 1 of 7	ENSP00000317106.4	Q13505-2
	MTX1	ENST00000609421.1	TSL:1	c.-20C>G		upstream_gene	N/A	ENSP00000476632.1	Q13505-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.69e-7 AC: 1 AN: 1299568 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 630568

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

African (AFR) AF: 0.00 AC: 0 AN: 27586

American (AMR) AF: 0.00 AC: 0 AN: 20900

Ashkenazi Jewish (ASJ) AF: 0.0000529 AC: 1 AN: 18904

East Asian (EAS) AF: 0.00 AC: 0 AN: 34280

South Asian (SAS) AF: 0.00 AC: 0 AN: 64716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43960

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1030872

Other (OTH) AF: 0.00 AC: 0 AN: 53596

⚠️ 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.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.045	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.97	L
PhyloP100		1.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.37
MutPred		0.47		Gain of MoRF binding (P = 5e-04)
MVP		0.48
MPC		0.90
ClinPred		0.96	D
GERP RS		4.5
PromoterAI		-0.91	Under-expression
Varity_R		0.19
gMVP		0.22
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs746148105; hg19: chr1-155179023;