11-102401552-G-A

Position:

• chr11-102401552-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000398136.7(TMEM123):​c.589C>T​(p.Arg197Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000279 in 1,431,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: TMEM123 ENST00000398136.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.46

Genes affected

TMEM123 (HGNC:30138): (transmembrane protein 123) This gene encodes a highly glycosylated transmembrane protein with a high content of threonine and serine residues in its extracellular domain, similar to a broadly defined category of proteins termed mucins. Exposure of some cell types to anti-PORIMIN (pro-oncosis receptor inducing membrane injury) antibody, crosslinks this protein on the cell surface and induces a type of cell death termed oncosis. Oncosis is distinct from apoptosis and is characterized by a loss of cell membrane integrity without DNA fragmentation. This gene product is proposed to function as a cell surface receptor that mediates cell death. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36031497).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM123	NM_052932.3	c.589C>T	p.Arg197Trp	missense_variant	4/5	ENST00000398136.7	NP_443164.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM123	ENST00000398136.7	c.589C>T	p.Arg197Trp	missense_variant	4/5	1	NM_052932.3	ENSP00000381204	P2
TMEM123	ENST00000361236.7	c.532C>T	p.Arg178Trp	missense_variant	3/4	1		ENSP00000355285
TMEM123	ENST00000528969.5	c.325C>T	p.Arg109Trp	missense_variant	4/5	4		ENSP00000434976	A2
TMEM123	ENST00000532161.5	c.325C>T	p.Arg109Trp	missense_variant	4/5	3		ENSP00000435331	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000279 AC: 4 AN: 1431208 Hom.: 0 Cov.: 31 AF XY: 0.00000562 AC XY: 4 AN XY: 711808

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: 0.00000362

Gnomad4 OTH exome AF: 0.00

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

Nov 14, 2023

The c.589C>T (p.R197W) alteration is located in exon 4 (coding exon 4) of the TMEM123 gene. This alteration results from a C to T substitution at nucleotide position 589, causing the arginine (R) at amino acid position 197 to be replaced by a tryptophan (W). 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	Uncertain	0.55
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	.;D;T;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;.;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.36	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.7	.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-5.5	D;D;D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D
Polyphen		0.95	P;P;.;.
Vest4		0.51
MutPred		0.60		.;Loss of disorder (P = 0.0241);.;.;
MVP		0.27
MPC		0.22
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.38
gMVP		0.50

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: rs1343957213; hg19: chr11-102272283;