NM_002455.5:c.19C>T

Variant names:

• chr1-155208823-C-T
• rs377309496
• NM_002455.5:c.19C>T

Variant summary

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

The NM_002455.5(MTX1):​c.19C>T​(p.Pro7Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000191 in 1,574,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MTX1 NM_002455.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.19
• 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=0.38234794).

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.19C>T	p.Pro7Ser	missense	Exon 1 of 8	NP_002446.3
	MTX1	NM_198883.3		c.19C>T	p.Pro7Ser	missense	Exon 1 of 7	NP_942584.2	Q13505-2
	THBS3	NM_001407556.1		c.-36+83G>A		intron	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.19C>T	p.Pro7Ser	missense	Exon 1 of 8	ENSP00000357360.3	Q13505-1
	MTX1	ENST00000316721.8	TSL:1	c.19C>T	p.Pro7Ser	missense	Exon 1 of 7	ENSP00000317106.4	Q13505-2
	THBS3	ENST00000486260.5	TSL:5	n.146+83G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00000475 AC: 1 AN: 210702 AF XY: 0.00000849

Gnomad AFR exome AF: 0.0000841

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1421792 Hom.: 0 Cov.: 34 AF XY: 0.00000285 AC XY: 2 AN XY: 702974

African (AFR) AF: 0.00 AC: 0 AN: 31620

American (AMR) AF: 0.00 AC: 0 AN: 39634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24688

East Asian (EAS) AF: 0.00 AC: 0 AN: 38218

South Asian (SAS) AF: 0.00 AC: 0 AN: 83718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50654

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5560

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1089420

Other (OTH) AF: 0.00 AC: 0 AN: 58280

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74378

African (AFR) AF: 0.0000241 AC: 1 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.000242 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000840 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.037	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.58	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.90	L
PhyloP100		2.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.32
MVP		0.82
MPC		0.24
ClinPred		0.68	D
GERP RS		4.5
PromoterAI		-0.027	Neutral
Varity_R		0.21
gMVP		0.24
Mutation Taster		=84/16	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: rs377309496; hg19: chr1-155178614;