Genetic Variant TMEM192:p.Leu155Arg (chr4-165088578-A-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001100389.2(TMEM192):c.464T>G(p.Leu155Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,612,966 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

TMEM192
NM_001100389.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.11

Variant links:

Genes affected

TMEM192 (HGNC:26775): (transmembrane protein 192) Enables protein homodimerization activity. Located in several cellular components, including late endosome; lysosomal membrane; and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

TMEM192 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM192	NM_001100389.2 link	c.464T>G	p.Leu155Arg	missense_variant	Exon 4 of 6	ENST00000306480.11	NP_001093859.1	Q8IY95-1
TMEM192	XM_011531718.4 link	c.440-2890T>G		intron_variant	Intron 3 of 4		XP_011530020.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMEM192	ENST00000306480.11 link	c.464T>G	p.Leu155Arg	missense_variant	Exon 4 of 6	1	NM_001100389.2	ENSP00000305069.4	Q8IY95-1
TMEM192	ENST00000506087.5 link	c.452T>G	p.Leu151Arg	missense_variant	Exon 5 of 7	2		ENSP00000425335.1	Q8IY95-2
TMEM192	ENST00000505095.1 link	c.41T>G	p.Leu14Arg	missense_variant	Exon 5 of 6	3		ENSP00000424590.1	D6RAZ6

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000407

AC:

AN:

245414

Hom.:

AF XY:

0.00

AC XY:

AN XY:

133146

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000896

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1460710

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

726544

show subpopulations

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:

0.0000225

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 16, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.464T>G (p.L155R) alteration is located in exon 4 (coding exon 4) of the TMEM192 gene. This alteration results from a T to G substitution at nucleotide position 464, causing the leucine (L) at amino acid position 155 to be replaced by an arginine (R). 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

0.41

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

T;.;.

Eigen

Uncertain

0.29

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Benign

0.0066

MetaRNN

Uncertain

0.67

D;D;D

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.7

M;.;.

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.2

D;D;D

REVEL

Uncertain

0.42

Sift

Uncertain

0.0040

D;D;D

Sift4G

Uncertain

0.0050

D;D;.

Polyphen

0.99

D;.;.

Vest4

0.97

MutPred

0.61

Loss of catalytic residue at Q158 (P = 0.1025);.;.;

MVP

0.26

MPC

0.16

ClinPred

0.94

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.47

gMVP

0.71

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