11-57712800-TTGAC-T

Position:

• chr11-57712800-TTGAC-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_015959.4(TMX2):​c.185_188delACTG​(p.Asp62fs) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,720 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: TMX2 NM_015959.4 frameshift, splice_region
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.46

Genes affected

TMX2 (HGNC:30739): (thioredoxin related transmembrane protein 2) This gene encodes a member of the disulfide isomerase (PDI) family of endoplasmic reticulum (ER) proteins that catalyze protein folding and thiol-disulfide interchange reactions. The encoded protein has an N-terminal ER-signal sequence, a catalytically active thioredoxin domain, one transmembrane domain and a C-terminal ER-retention sequence. This protein is enriched on the mitochondria-associated-membrane of the ER via palmitoylation of two of its cytosolically exposed cysteines. [provided by RefSeq, Jan 2017]

ENSG00000288534 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-57712800-TTGAC-T is Pathogenic according to our data. Variant chr11-57712800-TTGAC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3024111.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMX2	NM_015959.4	c.185_188delACTG	p.Asp62fs	frameshift_variant, splice_region_variant	1/8	ENST00000278422.9	NP_057043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMX2	ENST00000278422.9	c.185_188delACTG	p.Asp62fs	frameshift_variant, splice_region_variant	1/8	1	NM_015959.4	ENSP00000278422.4
ENSG00000288534	ENST00000674060.1	n.38_41delACTG		splice_region_variant, non_coding_transcript_exon_variant	1/20			ENSP00000501055.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461720 Hom.: 0 AF XY: 0.0000110 AC XY: 8 AN XY: 727152

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The frameshift c.185_188del (p.Asp62GlyfsTer7) variant in TMX2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant causes a frameshift starting with codon Aspartic Acid 62, changes this amino acid to Glycine residue, and creates a premature Stop codon at position 7 of the new reading frame, denoted p.Asp62GlyfsTer7. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-57480272;