11-102452613-C-A

Variant names:

• chr11-102452613-C-A
• rs746385427
• NM_052932.3:c.11G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_052932.3(TMEM123):​c.11G>T​(p.Gly4Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,555,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G4R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: TMEM123 NM_052932.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.49
• Publications: 0 publications found

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]

TMEM123-DT (HGNC:55502): (TMEM123 divergent transcript)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1955877).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052932.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM123	NM_052932.3	MANE Select	c.11G>T	p.Gly4Val	missense	Exon 1 of 5	NP_443164.2	Q8N131-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM123	ENST00000398136.7	TSL:1 MANE Select	c.11G>T	p.Gly4Val	missense	Exon 1 of 5	ENSP00000381204.2	Q8N131-1
	TMEM123	ENST00000361236.7	TSL:1	c.11G>T	p.Gly4Val	missense	Exon 1 of 4	ENSP00000355285.3	Q8N131-2
	TMEM123	ENST00000969654.1		c.11G>T	p.Gly4Val	missense	Exon 1 of 5	ENSP00000639713.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000473 AC: 9 AN: 190448 AF XY: 0.0000470

Gnomad AFR exome AF: 0.000103

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000803

Gnomad OTH exome AF: 0.000216

GnomAD4 exome AF: 0.000113 AC: 158 AN: 1403442 Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 75 AN XY: 697620

African (AFR) AF: 0.0000323 AC: 1 AN: 30976

American (AMR) AF: 0.00 AC: 0 AN: 41426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24906

East Asian (EAS) AF: 0.00 AC: 0 AN: 36232

South Asian (SAS) AF: 0.00 AC: 0 AN: 81010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5586

European-Non Finnish (NFE) AF: 0.000140 AC: 152 AN: 1085988

Other (OTH) AF: 0.0000866 AC: 5 AN: 57760

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74384

African (AFR) AF: 0.00 AC: 0 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000144 Hom.: 0

Bravo AF: 0.0000831

ExAC AF: 0.0000421 AC: 5

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Benign	0.080	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.065
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.5
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.10
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.16	T
Polyphen		1.0	D
Vest4		0.37
MVP		0.043
MPC		0.043
ClinPred		0.17	T
GERP RS		3.6
PromoterAI		0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.28
gMVP		0.40
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs746385427; hg19: chr11-102323344;