1-155209016-C-G

Position:

• chr1-155209016-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002455.5(MTX1):​c.212C>G​(p.Ala71Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTX1 NM_002455.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.173

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11575347).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTX1	NM_002455.5	c.212C>G	p.Ala71Gly	missense_variant	1/8	ENST00000368376.8	NP_002446.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTX1	ENST00000368376.8	c.212C>G	p.Ala71Gly	missense_variant	1/8	1	NM_002455.5	ENSP00000357360.3
MTX1	ENST00000316721.8	c.212C>G	p.Ala71Gly	missense_variant	1/7	1		ENSP00000317106.4
THBS3	ENST00000486260.5	n.36G>C		non_coding_transcript_exon_variant	1/14	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 30, 2023

The c.212C>G (p.A71G) alteration is located in exon 1 (coding exon 1) of the MTX1 gene. This alteration results from a C to G substitution at nucleotide position 212, causing the alanine (A) at amino acid position 71 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.022	T;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.39	T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;L
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.65	N;N
REVEL	Benign	0.028
Sift	Uncertain	0.013	D;D
Sift4G	Benign	0.070	T;T
Polyphen		0.68	P;P
Vest4		0.062
MutPred		0.27		Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);
MVP		0.23
MPC		0.43
ClinPred		0.38	T
GERP RS		3.6
Varity_R		0.045
gMVP		0.072

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

LitVar

Other links and lift over

dbSNP: rs749552182; hg19: chr1-155178807;