rs6971

Variant names:

• chr22-43162920-A-G
• rs6971
• NM_000714.6:c.439A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000714.6(TSPO):​c.439A>G​(p.Thr147Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.712 in 1,593,126 control chromosomes in the GnomAD database, including 408,706 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Synonymous variant affecting the same amino acid position (i.e. T147T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.75 (43147 hom., cov: 35)
  • Exomes 𝑓: 0.71 (365559 hom.)
• Consequence: TSPO NM_000714.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.42

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=1.0709306E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.947 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPO	NM_000714.6	c.439A>G	p.Thr147Ala	missense_variant	Exon 4 of 4	ENST00000337554.8	NP_000705.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSPO	ENST00000337554.8	c.439A>G	p.Thr147Ala	missense_variant	Exon 4 of 4	1	NM_000714.6	ENSP00000338004.3
TSPO	ENST00000583777.5	c.127A>G	p.Thr43Ala	missense_variant	Exon 3 of 3	1		ENSP00000463495.1
TSPO	ENST00000329563.8	c.439A>G	p.Thr147Ala	missense_variant	Exon 4 of 4	3		ENSP00000328973.4
TSPO	ENST00000396265.4	c.439A>G	p.Thr147Ala	missense_variant	Exon 4 of 4	5		ENSP00000379563.4

Frequencies

GnomAD3 genomes AF: 0.749 AC: 113905 AN: 152134 Hom.: 43087 Cov.: 35

Gnomad AFR AF: 0.813

Gnomad AMI AF: 0.693

Gnomad AMR AF: 0.806

Gnomad ASJ AF: 0.705

Gnomad EAS AF: 0.969

Gnomad SAS AF: 0.848

Gnomad FIN AF: 0.670

Gnomad MID AF: 0.693

Gnomad NFE AF: 0.688

Gnomad OTH AF: 0.759

GnomAD2 exomes AF: 0.758 AC: 164158 AN: 216438 AF XY: 0.755

Gnomad AFR exome AF: 0.803

Gnomad AMR exome AF: 0.863

Gnomad ASJ exome AF: 0.702

Gnomad EAS exome AF: 0.977

Gnomad FIN exome AF: 0.672

Gnomad NFE exome AF: 0.681

Gnomad OTH exome AF: 0.734

GnomAD4 exome AF: 0.709 AC: 1020986 AN: 1440874 Hom.: 365559 Cov.: 83 AF XY: 0.712 AC XY: 509157 AN XY: 714894

Gnomad4 AFR exome AF: 0.811 AC: 26825 AN: 33086

Gnomad4 AMR exome AF: 0.855 AC: 35843 AN: 41914

Gnomad4 ASJ exome AF: 0.700 AC: 18050 AN: 25776

Gnomad4 EAS exome AF: 0.972 AC: 37511 AN: 38606

Gnomad4 SAS exome AF: 0.842 AC: 70041 AN: 83176

Gnomad4 FIN exome AF: 0.682 AC: 34856 AN: 51122

Gnomad4 NFE exome AF: 0.681 AC: 750310 AN: 1102008

Gnomad4 Remaining exome AF: 0.728 AC: 43298 AN: 59502

GnomAD4 genome AF: 0.749 AC: 114025 AN: 152252 Hom.: 43147 Cov.: 35 AF XY: 0.752 AC XY: 55990 AN XY: 74446

Gnomad4 AFR AF: 0.813 AC: 0.813072 AN: 0.813072

Gnomad4 AMR AF: 0.807 AC: 0.806747 AN: 0.806747

Gnomad4 ASJ AF: 0.705 AC: 0.704729 AN: 0.704729

Gnomad4 EAS AF: 0.969 AC: 0.969498 AN: 0.969498

Gnomad4 SAS AF: 0.847 AC: 0.847493 AN: 0.847493

Gnomad4 FIN AF: 0.670 AC: 0.669966 AN: 0.669966

Gnomad4 NFE AF: 0.688 AC: 0.688156 AN: 0.688156

Gnomad4 OTH AF: 0.761 AC: 0.760664 AN: 0.760664

Alfa AF: 0.707 Hom.: 117388

Bravo AF: 0.762

TwinsUK AF: 0.672 AC: 2492

ALSPAC AF: 0.687 AC: 2649

ESP6500AA AF: 0.802 AC: 3526

ESP6500EA AF: 0.687 AC: 5905

ExAC AF: 0.738 AC: 88110

Asia WGS AF: 0.890 AC: 3095 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	14
DANN	Benign	0.65
DEOGEN2	Benign	0.036	T;.;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.30	.;T;.;T
MetaRNN	Benign	0.0000011	T;T;T;T
MetaSVM	Benign	-0.97	T
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	3.7	N;.;N;.
REVEL	Benign	0.16
Sift	Benign	1.0	T;.;T;.
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.14
MPC		0.21
ClinPred		0.021	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.097
gMVP		0.60
Mutation Taster		=85/15	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6971; hg19: chr22-43558926; COSMIC: COSV53355454; COSMIC: COSV53355454;