2-176323464-GGTAA-G

Variant names:

• chr2-176323464-GGTAA-G
• rs1575058847
• NM_006554.5:c.208+3_208+6delAAGT

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The ENST00000249442.11(MTX2):​c.208+1_208+4delGTAA variant causes a splice donor, splice region, intron change. The variant allele was found at a frequency of 0.000000686 in 1,456,762 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MTX2 ENST00000249442.11 splice_donor, splice_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.13

Genes affected

MTX2 (HGNC:7506): (metaxin 2) The protein encoded by this gene is highly similar to the metaxin 2 protein from mouse, which has been shown to interact with the mitochondrial membrane protein metaxin 1. Because of this similarity, it is thought that the encoded protein is peripherally associated with the cytosolic face of the outer mitochondrial membrane, and that it is involved in the import of proteins into the mitochondrion. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 7. [provided by RefSeq, Jun 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.09217171 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5, offset of 0 (no position change), new splice context is: ctgGTgtgt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-176323464-GGTAA-G is Pathogenic according to our data. Variant chr2-176323464-GGTAA-G is described in ClinVar as [Pathogenic]. Clinvar id is 805938.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTX2	NM_006554.5	c.208+3_208+6delAAGT		splice_region_variant, intron_variant	Intron 4 of 9	ENST00000249442.11	NP_006545.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTX2	ENST00000249442.11	c.208+1_208+4delGTAA		splice_donor_variant, splice_region_variant, intron_variant	Intron 4 of 9	1	NM_006554.5	ENSP00000249442.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456762 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 724820

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Progeroid mandibuloacral dysplasia Pathogenic:1

Nov 01, 2017

Marseille Medical Genetics, U1251, Aix Marseille University, Inserm

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Mandibuloacral dysplasia progeroid syndrome Pathogenic:1

Jan 04, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.96		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1575058847; hg19: chr2-177188192;