ENST00000681750.1:c.-169C>G

Variant names:

• chr9-32550898-G-C
• rs61758066
• ENST00000681750.1:c.-169C>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000681750.1(ENSG00000288684):​c.-169C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00986 in 1,612,974 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (7 hom., cov: 32)
  • Exomes 𝑓: 0.010 (100 hom.)
• Consequence: ENSG00000288684 ENST00000681750.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.417
• Publications: 11 publications found

Genes affected

ENSG00000288684 (HGNC:):

TOPORS (HGNC:21653): (TOP1 binding arginine/serine rich protein, E3 ubiquitin ligase) This gene encodes a nuclear protein which is serine and arginine rich, and contains a RING-type zinc finger domain. It is highly expressed in the testis, and functions as an ubiquitin-protein E3 ligase. Mutations in this gene are associated with retinitis pigmentosa type 31. Alternatively spliced transcript variants, encoding different isoforms, have been observed for this locus. [provided by RefSeq, Sep 2010]

SMIM27 (HGNC:31420): (small integral membrane protein 27) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037550926).
• BP6: Variant 9-32550898-G-C is Benign according to our data. Variant chr9-32550898-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 195250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 7 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000681750.1. 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
	TOPORS	NM_005802.5	MANE Select	c.74C>G	p.Ser25Trp	missense	Exon 2 of 3	NP_005793.2
	TOPORS	NM_001195622.2		c.3+1536C>G		intron	N/A	NP_001182551.1	Q9NS56-2
	SMIM27	NM_001349118.1		c.-997G>C		upstream_gene	N/A	NP_001336047.1	A0A1B0GUW7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000288684	ENST00000681750.1		c.-169C>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 20	ENSP00000506413.1	A0A7P0TB70
	TOPORS	ENST00000360538.7	TSL:1 MANE Select	c.74C>G	p.Ser25Trp	missense	Exon 2 of 3	ENSP00000353735.2	Q9NS56-1
	ENSG00000288684	ENST00000681750.1		c.-169C>G		5_prime_UTR	Exon 3 of 20	ENSP00000506413.1	A0A7P0TB70

Frequencies

GnomAD3 genomes AF: 0.00694 AC: 1057 AN: 152216 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0203

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0102

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00825 AC: 2001 AN: 242688 AF XY: 0.00817

Gnomad AFR exome AF: 0.00180

Gnomad AMR exome AF: 0.00643

Gnomad ASJ exome AF: 0.00143

Gnomad EAS exome AF: 0.000612

Gnomad FIN exome AF: 0.0230

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.00685

GnomAD4 exome AF: 0.0102 AC: 14853 AN: 1460640 Hom.: 100 Cov.: 31 AF XY: 0.0100 AC XY: 7269 AN XY: 726682

African (AFR) AF: 0.00167 AC: 56 AN: 33464

American (AMR) AF: 0.00582 AC: 260 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00153 AC: 40 AN: 26102

East Asian (EAS) AF: 0.000529 AC: 21 AN: 39692

South Asian (SAS) AF: 0.00186 AC: 160 AN: 86246

European-Finnish (FIN) AF: 0.0220 AC: 1154 AN: 52538

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.0114 AC: 12661 AN: 1111792

Other (OTH) AF: 0.00817 AC: 493 AN: 60338

GnomAD4 genome AF: 0.00693 AC: 1056 AN: 152334 Hom.: 7 Cov.: 32 AF XY: 0.00713 AC XY: 531 AN XY: 74500

African (AFR) AF: 0.00156 AC: 65 AN: 41588

American (AMR) AF: 0.00359 AC: 55 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5170

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4834

European-Finnish (FIN) AF: 0.0203 AC: 216 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0102 AC: 691 AN: 68020

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00390 Hom.: 1

Bravo AF: 0.00596

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00923 AC: 79

ExAC AF: 0.00811 AC: 982

EpiCase AF: 0.00911

EpiControl AF: 0.0101

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)
-	-	1	Retinal dystrophy (1)
-	-	1	Retinitis pigmentosa (1)
-	-	1	Retinitis pigmentosa 31 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0078	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.42
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.067
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.021	D
Polyphen		0.69	P
Vest4		0.33
MVP		0.19
MPC		0.73
ClinPred		0.020	T
GERP RS		3.4
PromoterAI		0.062	Neutral
Varity_R		0.073
gMVP		0.55
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs61758066; hg19: chr9-32550896; COSMIC: COSV62118544; COSMIC: COSV62118544;