chr1-155209159-G-C

Variant names:

• chr1-155209159-G-C
• rs772881234
• NM_002455.5:c.355G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002455.5(MTX1):​c.355G>C​(p.Ala119Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000074 in 1,351,072 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A119T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: MTX1 NM_002455.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.26
• 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: 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=0.06555906).

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.355G>C	p.Ala119Pro	missense	Exon 1 of 8	NP_002446.3
	MTX1	NM_198883.3		c.355G>C	p.Ala119Pro	missense	Exon 1 of 7	NP_942584.2	Q13505-2
	THBS3	NM_001407556.1		c.-289C>G		5_prime_UTR	Exon 1 of 23	NP_001394485.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTX1	ENST00000368376.8	TSL:1 MANE Select	c.355G>C	p.Ala119Pro	missense	Exon 1 of 8	ENSP00000357360.3	Q13505-1
	MTX1	ENST00000316721.8	TSL:1	c.355G>C	p.Ala119Pro	missense	Exon 1 of 7	ENSP00000317106.4	Q13505-2
	MTX1	ENST00000609421.1	TSL:1	c.-93G>C		upstream_gene	N/A	ENSP00000476632.1	Q13505-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.40e-7 AC: 1 AN: 1351072 Hom.: 0 Cov.: 34 AF XY: 0.00000151 AC XY: 1 AN XY: 662540

African (AFR) AF: 0.00 AC: 0 AN: 29280

American (AMR) AF: 0.00 AC: 0 AN: 27572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22576

East Asian (EAS) AF: 0.00 AC: 0 AN: 34708

South Asian (SAS) AF: 0.00 AC: 0 AN: 74508

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46200

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4620

European-Non Finnish (NFE) AF: 9.47e-7 AC: 1 AN: 1055932

Other (OTH) AF: 0.00 AC: 0 AN: 55676

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.73
DANN	Benign	0.86
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0023	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		-1.3
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.0060
Sift	Benign	0.24	T
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.031
MutPred		0.24		Gain of loop (P = 0.0079)
MVP		0.26
MPC		0.31
ClinPred		0.093	T
GERP RS		-1.9
PromoterAI		-0.15	Neutral
Varity_R		0.074
gMVP		0.19
Mutation Taster		=96/4	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: rs772881234; hg19: chr1-155178950;