17-75517101-CGCCCTCCCTGCCCTCCCT-CGCCCTCCCT

Variant names:

• chr17-75517101-CGCCCTCCCT-C
• rs58038334
• NM_207346.3:c.286-41_286-33delGCCCTCCCT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_207346.3(TSEN54):​c.286-41_286-33delGCCCTCCCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 1,540,818 control chromosomes in the GnomAD database, including 19,205 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4677 hom., cov: 27)
  • Exomes 𝑓: 0.14 (14528 hom.)
• Consequence: TSEN54 NM_207346.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.53
• Publications: 0 publications found

Genes affected

TSEN54 (HGNC:27561): (tRNA splicing endonuclease subunit 54) This gene encodes a subunit of the tRNA splicing endonuclease complex, which catalyzes the removal of introns from precursor tRNAs. The complex is also implicated in pre-mRNA 3-prime end processing. Mutations in this gene result in pontocerebellar hypoplasia type 2.[provided by RefSeq, Oct 2009]

TSEN54 Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia type 2A

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• pontocerebellar hypoplasia type 4

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia
• pontocerebellar hypoplasia type 5

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• pontocerebellar hypoplasia type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP6: Variant 17-75517101-CGCCCTCCCT-C is Benign according to our data. Variant chr17-75517101-CGCCCTCCCT-C is described in ClinVar as Benign. ClinVar VariationId is 263293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.413 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSEN54	NM_207346.3	c.286-41_286-33delGCCCTCCCT		intron_variant	Intron 3 of 10	ENST00000333213.11	NP_997229.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSEN54	ENST00000333213.11	c.286-41_286-33delGCCCTCCCT		intron_variant	Intron 3 of 10	1	NM_207346.3	ENSP00000327487.6

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32126 AN: 151100 Hom.: 4663 Cov.: 27

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.0200

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.0851

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.198

GnomAD2 exomes AF: 0.135 AC: 25338 AN: 188328 AF XY: 0.131

Gnomad AFR exome AF: 0.398

Gnomad AMR exome AF: 0.0990

Gnomad ASJ exome AF: 0.161

Gnomad EAS exome AF: 0.0781

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.128

Gnomad OTH exome AF: 0.139

GnomAD4 exome AF: 0.139 AC: 193280 AN: 1389602 Hom.: 14528 AF XY: 0.138 AC XY: 95189 AN XY: 688230

African (AFR) AF: 0.422 AC: 13407 AN: 31778

American (AMR) AF: 0.104 AC: 4059 AN: 39052

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 4250 AN: 25162

East Asian (EAS) AF: 0.0554 AC: 2067 AN: 37322

South Asian (SAS) AF: 0.136 AC: 10987 AN: 80506

European-Finnish (FIN) AF: 0.117 AC: 5589 AN: 47924

Middle Eastern (MID) AF: 0.162 AC: 908 AN: 5620

European-Non Finnish (NFE) AF: 0.135 AC: 143445 AN: 1064410

Other (OTH) AF: 0.148 AC: 8568 AN: 57828

GnomAD4 genome AF: 0.213 AC: 32177 AN: 151216 Hom.: 4677 Cov.: 27 AF XY: 0.209 AC XY: 15459 AN XY: 73946

African (AFR) AF: 0.418 AC: 17239 AN: 41214

American (AMR) AF: 0.146 AC: 2230 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 572 AN: 3452

East Asian (EAS) AF: 0.0847 AC: 435 AN: 5136

South Asian (SAS) AF: 0.141 AC: 679 AN: 4816

European-Finnish (FIN) AF: 0.107 AC: 1124 AN: 10518

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.139 AC: 9406 AN: 67548

Other (OTH) AF: 0.197 AC: 414 AN: 2106

Alfa AF: 0.0975 Hom.: 169

Bravo AF: 0.225

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 28, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs58038334; hg19: chr17-73513182; COSMIC: COSV58691263; COSMIC: COSV58691263;