17-58309371-C-T

Variant names:

• chr17-58309371-C-T
• rs61741210
• NM_004758.4:c.3901G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000343736.9(TSPOAP1):​c.3901G>A​(p.Asp1301Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 1,608,002 control chromosomes in the GnomAD database, including 541 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (33 hom., cov: 32)
  • Exomes 𝑓: 0.024 (508 hom.)
• Consequence: TSPOAP1 ENST00000343736.9 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.46
• Publications: 9 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002943635).
• BP6: Variant 17-58309371-C-T is Benign according to our data. Variant chr17-58309371-C-T is described in ClinVar as Benign. ClinVar VariationId is 402437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0183 (2777/152156) while in subpopulation SAS AF = 0.0305 (147/4816). AF 95% confidence interval is 0.0265. There are 33 homozygotes in GnomAd4. There are 1376 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000343736.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPOAP1	NM_004758.4	MANE Select	c.3901G>A	p.Asp1301Asn	missense	Exon 22 of 32	NP_004749.2
	TSPOAP1	NM_001261835.2		c.3901G>A	p.Asp1301Asn	missense	Exon 22 of 32	NP_001248764.1
	TSPOAP1	NM_024418.3		c.3721G>A	p.Asp1241Asn	missense	Exon 21 of 31	NP_077729.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPOAP1	ENST00000343736.9	TSL:1 MANE Select	c.3901G>A	p.Asp1301Asn	missense	Exon 22 of 32	ENSP00000345824.4
	TSPOAP1	ENST00000268893.10	TSL:1	c.3721G>A	p.Asp1241Asn	missense	Exon 21 of 31	ENSP00000268893.6
	TSPOAP1	ENST00000580669.6	TSL:5	c.1297G>A	p.Asp433Asn	missense	Exon 6 of 16	ENSP00000462822.2

Frequencies

GnomAD3 genomes AF: 0.0183 AC: 2779 AN: 152038 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.00394

Gnomad AMI AF: 0.0176

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.0545

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.0307

Gnomad FIN AF: 0.0239

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0245

Gnomad OTH AF: 0.0259

GnomAD2 exomes AF: 0.0226 AC: 5462 AN: 241648 AF XY: 0.0243

Gnomad AFR exome AF: 0.00387

Gnomad AMR exome AF: 0.0120

Gnomad ASJ exome AF: 0.0530

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0249

Gnomad NFE exome AF: 0.0252

Gnomad OTH exome AF: 0.0275

GnomAD4 exome AF: 0.0236 AC: 34343 AN: 1455846 Hom.: 508 Cov.: 34 AF XY: 0.0246 AC XY: 17827 AN XY: 723784

African (AFR) AF: 0.00392 AC: 131 AN: 33426

American (AMR) AF: 0.0126 AC: 563 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.0521 AC: 1354 AN: 25976

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39630

South Asian (SAS) AF: 0.0355 AC: 3058 AN: 86020

European-Finnish (FIN) AF: 0.0233 AC: 1177 AN: 50432

Middle Eastern (MID) AF: 0.0361 AC: 208 AN: 5764

European-Non Finnish (NFE) AF: 0.0238 AC: 26391 AN: 1109692

Other (OTH) AF: 0.0242 AC: 1456 AN: 60240

GnomAD4 genome AF: 0.0183 AC: 2777 AN: 152156 Hom.: 33 Cov.: 32 AF XY: 0.0185 AC XY: 1376 AN XY: 74386

African (AFR) AF: 0.00393 AC: 163 AN: 41524

American (AMR) AF: 0.0180 AC: 276 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0545 AC: 189 AN: 3468

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5158

South Asian (SAS) AF: 0.0305 AC: 147 AN: 4816

European-Finnish (FIN) AF: 0.0239 AC: 253 AN: 10586

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0245 AC: 1667 AN: 67998

Other (OTH) AF: 0.0256 AC: 54 AN: 2108

Alfa AF: 0.0237 Hom.: 143

Bravo AF: 0.0170

TwinsUK AF: 0.0218 AC: 81

ALSPAC AF: 0.0223 AC: 86

ESP6500AA AF: 0.00568 AC: 25

ESP6500EA AF: 0.0259 AC: 223

ExAC AF: 0.0224 AC: 2715

Asia WGS AF: 0.0120 AC: 40 AN: 3478

EpiCase AF: 0.0280

EpiControl AF: 0.0292

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T
Eigen	Benign	0.053
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.5
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.22
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.045	D
Polyphen		0.014	B
Vest4		0.28
MPC		0.21
ClinPred		0.011	T
GERP RS		5.6
Varity_R		0.13
gMVP		0.20
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs61741210; hg19: chr17-56386732; COSMIC: COSV52108620; COSMIC: COSV52108620;