Genetic Variant TMEM192:p.Arg124Gln (chr4-165100696-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001100389.2(TMEM192):c.371G>A(p.Arg124Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000682 in 1,614,040 control chromosomes in the GnomAD database, including 4 homozygotes. 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 0.00082 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00067 ( 2 hom. )

Consequence

TMEM192
NM_001100389.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.914

Publications

6 publications found

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 was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04054928).

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001100389.2. 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
	TMEM192	NM_001100389.2	MANE Select	c.371G>A	p.Arg124Gln	missense	Exon 3 of 6	NP_001093859.1	Q8IY95-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM192	ENST00000306480.11	TSL:1 MANE Select	c.371G>A	p.Arg124Gln	missense	Exon 3 of 6	ENSP00000305069.4	Q8IY95-1
TMEM192	ENST00000506087.5	TSL:2	c.359G>A	p.Arg120Gln	missense	Exon 4 of 7	ENSP00000425335.1	Q8IY95-2
TMEM192	ENST00000892790.1		c.371G>A	p.Arg124Gln	missense	Exon 3 of 5	ENSP00000562849.1

Frequencies

GnomAD3 genomes

AF:

0.000822

AC:

125

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00321

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:

0.000897

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000473

AC:

118

AN:

249532

AF XY:

0.000399

show subpopulations

Gnomad AFR exome

AF:

0.000258

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000645

Gnomad OTH exome

AF:

0.000660

GnomAD4 exome

AF:

0.000667

AC:

975

AN:

1461864

Hom.:

Cov.:

AF XY:

0.000646

AC XY:

470

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.00101

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000794

AC:

883

AN:

1112000

Other (OTH)

AF:

0.000695

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

116

174

232

290

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000821

AC:

125

AN:

152176

Hom.:

Cov.:

AF XY:

0.000873

AC XY:

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41524

American (AMR)

AF:

0.00321

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000897

AC:

AN:

68024

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000652

Hom.:

Bravo

AF:

0.000801

ESP6500AA

AF:

0.00106

AC:

ESP6500EA

AF:

0.000485

AC:

ExAC

AF:

0.000356

AC:

EpiCase

AF:

0.000872

EpiControl

AF:

0.00101

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.051

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.84

M_CAP

Benign

0.0023

MetaRNN

Benign

0.041

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PhyloP100

0.91

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.5

REVEL

Benign

0.040

Sift

Benign

0.076

Sift4G

Benign

0.095

Polyphen

0.55

Vest4

0.19

MVP

0.076

MPC

0.025

ClinPred

0.024

GERP RS

0.57

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.041

gMVP

0.37

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over