Genetic Variant NM_000714.6:c.485G>A (chr22-43162966-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000714.6(TSPO):c.485G>A(p.Arg162His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 1,587,552 control chromosomes in the GnomAD database, including 47,534 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.19 ( 3338 hom., cov: 34)

Exomes 𝑓: 0.24 ( 44196 hom. )

Consequence

TSPO
NM_000714.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.05

Publications

39 publications found

Variant links:

Genes affected

TSPO (HGNC:1158): (translocator protein) Present mainly in the mitochondrial compartment of peripheral tissues, the protein encoded by this gene interacts with some benzodiazepines and has different affinities than its endogenous counterpart. The protein is a key factor in the flow of cholesterol into mitochondria to permit the initiation of steroid hormone synthesis. Alternatively spliced transcript variants have been reported; one of the variants lacks an internal exon and is considered non-coding, and the other variants encode the same protein. [provided by RefSeq, Feb 2012]

TSPO links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0048539937).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPO	NM_000714.6 link	c.485G>A	p.Arg162His	missense_variant	Exon 4 of 4	ENST00000337554.8	NP_000705.2	P30536-1O76068

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TSPO	ENST00000337554.8 link	c.485G>A	p.Arg162His	missense_variant	Exon 4 of 4	1	NM_000714.6	ENSP00000338004.3	P30536-1
TSPO	ENST00000583777.5 link	c.173G>A	p.Arg58His	missense_variant	Exon 3 of 3	1		ENSP00000463495.1	J3QLD3
TSPO	ENST00000329563.8 link	c.485G>A	p.Arg162His	missense_variant	Exon 4 of 4	3		ENSP00000328973.4	P30536-1
TSPO	ENST00000396265.4 link	c.485G>A	p.Arg162His	missense_variant	Exon 4 of 4	5		ENSP00000379563.4	P30536-1

Frequencies

GnomAD3 genomes

AF:

0.194

AC:

29519

AN:

152122

Hom.:

3334

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0806

Gnomad AMI

AF:

0.305

Gnomad AMR

AF:

0.169

Gnomad ASJ

AF:

0.222

Gnomad EAS

AF:

0.247

Gnomad SAS

AF:

0.323

Gnomad FIN

AF:

0.253

Gnomad MID

AF:

0.152

Gnomad NFE

AF:

0.244

Gnomad OTH

AF:

0.201

GnomAD2 exomes

AF:

0.232

AC:

47924

AN:

206152

AF XY:

0.243

show subpopulations

Gnomad AFR exome

AF:

0.0777

Gnomad AMR exome

AF:

0.161

Gnomad ASJ exome

AF:

0.226

Gnomad EAS exome

AF:

0.246

Gnomad FIN exome

AF:

0.251

Gnomad NFE exome

AF:

0.245

Gnomad OTH exome

AF:

0.243

GnomAD4 exome

AF:

0.245

AC:

351214

AN:

1435312

Hom.:

44196

Cov.:

AF XY:

0.248

AC XY:

176529

AN XY:

711958

show subpopulations

African (AFR)

AF:

0.0703

AC:

2316

AN:

32950

American (AMR)

AF:

0.162

AC:

6667

AN:

41156

Ashkenazi Jewish (ASJ)

AF:

0.224

AC:

5749

AN:

25718

East Asian (EAS)

AF:

0.239

AC:

9055

AN:

37966

South Asian (SAS)

AF:

0.315

AC:

26173

AN:

82982

European-Finnish (FIN)

AF:

0.254

AC:

12622

AN:

49788

Middle Eastern (MID)

AF:

0.239

AC:

1365

AN:

5712

European-Non Finnish (NFE)

AF:

0.249

AC:

273319

AN:

1099756

Other (OTH)

AF:

0.235

AC:

13948

AN:

59284

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

17430

34860

52291

69721

87151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9360

18720

28080

37440

46800

<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:

0.194

AC:

29530

AN:

152240

Hom.:

3338

Cov.:

AF XY:

0.195

AC XY:

14532

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0808

AC:

3357

AN:

41566

American (AMR)

AF:

0.169

AC:

2580

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.222

AC:

770

AN:

3468

East Asian (EAS)

AF:

0.246

AC:

1271

AN:

5164

South Asian (SAS)

AF:

0.321

AC:

1552

AN:

4830

European-Finnish (FIN)

AF:

0.253

AC:

2678

AN:

10592

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.244

AC:

16559

AN:

67998

Other (OTH)

AF:

0.210

AC:

443

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1227

2454

3681

4908

6135

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

334

668

1002

1336

1670

<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:

0.228

Hom.:

14240

Bravo

AF:

0.181

TwinsUK

AF:

0.252

AC:

935

ALSPAC

AF:

0.247

AC:

952

ESP6500AA

AF:

0.0853

AC:

373

ESP6500EA

AF:

0.235

AC:

2008

ExAC

AF:

0.202

AC:

23863

Asia WGS

AF:

0.265

AC:

920

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.022

T;.;T;T

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.083

LIST_S2

Benign

0.66

.;T;.;T

MetaRNN

Benign

0.0049

T;T;T;T

MetaSVM

Benign

-1.0

PhyloP100

1.0

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.5

N;.;N;.

REVEL

Benign

0.026

Sift

Benign

0.22

T;.;T;.

Sift4G

Benign

0.17

T;T;T;T

Polyphen

0.019

B;.;B;B

Vest4

0.17

MPC

0.27

ClinPred

0.011

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.076

gMVP

0.52

Mutation Taster

=95/5

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over