11-57712760-G-C

Position:

• chr11-57712760-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000278422.9(TMX2):​c.142G>C​(p.Gly48Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0042 in 1,614,112 control chromosomes in the GnomAD database, including 23 homozygotes. 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0043 (21 hom.)
• Consequence: TMX2 ENST00000278422.9 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 3.71

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]

TMX2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006521851).
• BP6: Variant 11-57712760-G-C is Benign according to our data. Variant chr11-57712760-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 2641793.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-57712760-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00296 (451/152294) while in subpopulation NFE AF= 0.00479 (326/68026). AF 95% confidence interval is 0.00436. There are 2 homozygotes in gnomad4. There are 217 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMX2	NM_015959.4	c.142G>C	p.Gly48Arg	missense_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.142G>C	p.Gly48Arg	missense_variant	1/8	1	NM_015959.4	ENSP00000278422.4
ENSG00000288534	ENST00000674060.1	n.-6G>C		upstream_gene_variant				ENSP00000501055.2

Frequencies

GnomAD3 genomes AF: 0.00296 AC: 451 AN: 152176 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00659

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00434

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00479

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00305 AC: 767 AN: 251206 Hom.: 3 AF XY: 0.00331 AC XY: 449 AN XY: 135854

Gnomad AFR exome AF: 0.000986

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00320

Gnomad FIN exome AF: 0.00504

Gnomad NFE exome AF: 0.00438

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00433 AC: 6324 AN: 1461818 Hom.: 21 Cov.: 31 AF XY: 0.00429 AC XY: 3117 AN XY: 727208

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.000939

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00364

Gnomad4 FIN exome AF: 0.00465

Gnomad4 NFE exome AF: 0.00496

Gnomad4 OTH exome AF: 0.00301

GnomAD4 genome AF: 0.00296 AC: 451 AN: 152294 Hom.: 2 Cov.: 33 AF XY: 0.00291 AC XY: 217 AN XY: 74468

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.00434

Gnomad4 NFE AF: 0.00479

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00287 Hom.: 1

Bravo AF: 0.00253

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00285 AC: 346

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00379

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2024

TMX2: BP4, BS2 -

TMX2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 13, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0065	.;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0065	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N;N
MutationTaster	Benign	0.75	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.23	N;N
REVEL	Benign	0.043
Sift	Benign	0.35	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.0	B;B
Vest4		0.34
MVP		0.22
MPC		0.33
ClinPred		0.055	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.047
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs111605325; hg19: chr11-57480232;