17-58307630-C-T

Variant names:

• chr17-58307630-C-T
• rs147089668
• NM_004758.4:c.4964G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004758.4(TSPOAP1):​c.4964G>A​(p.Arg1655Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,613,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00095 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (0 hom.)
• Consequence: TSPOAP1 NM_004758.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 B:1
• Conservation: PhyloP100: -0.270
• Publications: 1 publications found

Genes affected

TSPOAP1 (HGNC:16831): (TSPO associated protein 1) Enables benzodiazepine receptor binding activity. Predicted to be involved in regulation of presynaptic cytosolic calcium ion concentration. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

TSPOAP1 Gene-Disease associations (from GenCC):

• TH-deficient dopa-responsive dystonia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010245562).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004758.4. 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
	TSPOAP1	NM_004758.4	MANE Select	c.4964G>A	p.Arg1655Gln	missense	Exon 24 of 32	NP_004749.2	O95153-1
	TSPOAP1	NM_001261835.2		c.4964G>A	p.Arg1655Gln	missense	Exon 24 of 32	NP_001248764.1
	TSPOAP1	NM_024418.3		c.4784G>A	p.Arg1595Gln	missense	Exon 23 of 31	NP_077729.1	O95153-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPOAP1	ENST00000343736.9	TSL:1 MANE Select	c.4964G>A	p.Arg1655Gln	missense	Exon 24 of 32	ENSP00000345824.4	O95153-1
	TSPOAP1	ENST00000268893.10	TSL:1	c.4784G>A	p.Arg1595Gln	missense	Exon 23 of 31	ENSP00000268893.6	O95153-2
	TSPOAP1	ENST00000580669.6	TSL:5	c.2360G>A	p.Arg787Gln	missense	Exon 8 of 16	ENSP00000462822.2	J3KT64

Frequencies

GnomAD3 genomes AF: 0.000953 AC: 145 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00140

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000918 AC: 230 AN: 250680 AF XY: 0.000996

Gnomad AFR exome AF: 0.000556

Gnomad AMR exome AF: 0.000724

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.00132

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.00140 AC: 2048 AN: 1461606 Hom.: 0 Cov.: 32 AF XY: 0.00137 AC XY: 997 AN XY: 727058

African (AFR) AF: 0.000388 AC: 13 AN: 33478

American (AMR) AF: 0.000514 AC: 23 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.000574 AC: 15 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86232

European-Finnish (FIN) AF: 0.00124 AC: 66 AN: 53222

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00168 AC: 1873 AN: 1111980

Other (OTH) AF: 0.000878 AC: 53 AN: 60384

GnomAD4 genome AF: 0.000952 AC: 145 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.000859 AC XY: 64 AN XY: 74494

African (AFR) AF: 0.000529 AC: 22 AN: 41590

American (AMR) AF: 0.000588 AC: 9 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00169 AC: 18 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00140 AC: 95 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00123 Hom.: 1

Bravo AF: 0.000884

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.000766 AC: 93

EpiCase AF: 0.00142

EpiControl AF: 0.00113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)
-	-	1	TSPOAP1-related disorder (1)
-	1	-	TSPOAP1-related Dystonia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.27
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.044
Sift	Benign	0.45	T
Sift4G	Uncertain	0.054	T
Polyphen		0.10	B
Vest4		0.15
MVP		0.088
MPC		0.27
ClinPred		0.025	T
GERP RS		-0.89
Varity_R		0.036
gMVP		0.33
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs147089668; hg19: chr17-56384991; COSMIC: COSV52104085; COSMIC: COSV52104085;