11-102401681-T-G

Position:

chr11-102401681-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_052932.3(TMEM123):c.460A>C(p.Met154Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00014 in 1,593,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

TMEM123
NM_052932.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.331

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.039715707).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM123	NM_052932.3 linkuse as main transcript	c.460A>C	p.Met154Leu	missense_variant	4/5	ENST00000398136.7	NP_443164.2	Q8N131-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TMEM123	ENST00000398136.7 linkuse as main transcript	c.460A>C	p.Met154Leu	missense_variant	4/5	1	NM_052932.3	ENSP00000381204.2	Q8N131-1
TMEM123	ENST00000361236.7 linkuse as main transcript	c.403A>C	p.Met135Leu	missense_variant	3/4	1		ENSP00000355285.3	Q8N131-2
TMEM123	ENST00000528969.5 linkuse as main transcript	c.196A>C	p.Met66Leu	missense_variant	4/5	4		ENSP00000434976.1	E9PKT4
TMEM123	ENST00000532161.5 linkuse as main transcript	c.196A>C	p.Met66Leu	missense_variant	4/5	3		ENSP00000435331.1	E9PKT4

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.000176

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000528

AC:

AN:

227352

Hom.:

AF XY:

0.0000405

AC XY:

AN XY:

123596

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000361

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000102

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000142

AC:

205

AN:

1441174

Hom.:

Cov.:

AF XY:

0.000133

AC XY:

AN XY:

716688

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000533

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:

0.000178

Gnomad4 OTH exome

AF:

0.000101

GnomAD4 genome

AF:

0.000118

AC:

AN:

152042

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74258

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.0000983

Hom.:

Bravo

AF:

0.000128

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000246

AC:

ExAC

AF:

0.0000497

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2024

The c.460A>C (p.M154L) alteration is located in exon 4 (coding exon 4) of the TMEM123 gene. This alteration results from a A to C substitution at nucleotide position 460, causing the methionine (M) at amino acid position 154 to be replaced by a leucine (L). 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

Benign

0.092

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.67

CADD

Benign

1.8

DANN

Benign

0.74

DEOGEN2

Benign

0.044

.;T;T;T

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.069

LIST_S2

Benign

0.31

T;T;.;T

M_CAP

Benign

0.0069

MetaRNN

Benign

0.040

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.14

.;N;.;.

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.040

N;N;N;N

REVEL

Benign

0.016

Sift

Benign

0.33

T;T;T;T

Sift4G

Benign

0.40

T;T;T;T

Polyphen

0.0010

B;B;.;.

Vest4

0.14

MutPred

0.33

.;Loss of ubiquitination at K159 (P = 0.0573);.;.;

MVP

0.043

MPC

0.037

ClinPred

0.015

GERP RS

-0.53

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.033

gMVP

0.28

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over