NM_207346.3:c.624-37A>C

Variant names:

• chr17-75521668-A-C
• rs73998306
• NM_207346.3:c.624-37A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_207346.3(TSEN54):​c.624-37A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 1,608,944 control chromosomes in the GnomAD database, including 1,717 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.060 (871 hom., cov: 32)
  • Exomes 𝑓: 0.0066 (846 hom.)
• Consequence: TSEN54 NM_207346.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0230
• 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 -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-75521668-A-C is Benign according to our data. Variant chr17-75521668-A-C is described in ClinVar as Benign. ClinVar VariationId is 160137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207346.3. 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
	TSEN54	NM_207346.3	MANE Select	c.624-37A>C		intron	N/A	NP_997229.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN54	ENST00000333213.11	TSL:1 MANE Select	c.624-37A>C		intron	N/A	ENSP00000327487.6
	TSEN54	ENST00000580013.6	TSL:4	n.790A>C		non_coding_transcript_exon	Exon 7 of 9
	TSEN54	ENST00000679370.1		n.1168A>C		non_coding_transcript_exon	Exon 7 of 9

Frequencies

GnomAD3 genomes AF: 0.0600 AC: 9126 AN: 152028 Hom.: 867 Cov.: 32

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0299

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00125

Gnomad OTH AF: 0.0494

GnomAD2 exomes AF: 0.0165 AC: 4094 AN: 248736 AF XY: 0.0121

Gnomad AFR exome AF: 0.214

Gnomad AMR exome AF: 0.0125

Gnomad ASJ exome AF: 0.00340

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000925

Gnomad OTH exome AF: 0.00981

GnomAD4 exome AF: 0.00655 AC: 9549 AN: 1456798 Hom.: 846 Cov.: 29 AF XY: 0.00567 AC XY: 4114 AN XY: 725000

African (AFR) AF: 0.214 AC: 7154 AN: 33352

American (AMR) AF: 0.0148 AC: 661 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00338 AC: 88 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.000545 AC: 47 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52752

Middle Eastern (MID) AF: 0.0113 AC: 65 AN: 5760

European-Non Finnish (NFE) AF: 0.000622 AC: 689 AN: 1108118

Other (OTH) AF: 0.0140 AC: 845 AN: 60220

GnomAD4 genome AF: 0.0601 AC: 9144 AN: 152146 Hom.: 871 Cov.: 32 AF XY: 0.0583 AC XY: 4336 AN XY: 74404

African (AFR) AF: 0.204 AC: 8472 AN: 41460

American (AMR) AF: 0.0298 AC: 456 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00125 AC: 85 AN: 67994

Other (OTH) AF: 0.0489 AC: 103 AN: 2106

Alfa AF: 0.0196 Hom.: 93

Bravo AF: 0.0690

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Jun 30, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.6
DANN	Benign	0.75
PhyloP100		-0.023
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs73998306; hg19: chr17-73517749;