chr17-75517596-A-C

Variant names:

• chr17-75517596-A-C
• rs11559205
• NM_207346.3:c.409A>C

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.409A>C​(p.Ile137Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0724 in 1,613,612 control chromosomes in the GnomAD database, including 5,068 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.097 (975 hom., cov: 32)
  • Exomes 𝑓: 0.070 (4093 hom.)
• Consequence: TSEN54 NM_207346.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.54
• Publications: 20 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 5

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• pontocerebellar hypoplasia type 4

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP6: Variant 17-75517596-A-C is Benign according to our data. Variant chr17-75517596-A-C is described in ClinVar as Benign. ClinVar VariationId is 160134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.172 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN54	NM_207346.3	MANE Select	c.409A>C	p.Ile137Leu	missense	Exon 5 of 11	NP_997229.2	Q7Z6J9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN54	ENST00000333213.11	TSL:1 MANE Select	c.409A>C	p.Ile137Leu	missense	Exon 5 of 11	ENSP00000327487.6	Q7Z6J9-1
	TSEN54	ENST00000680999.1		c.409A>C	p.Ile137Leu	missense	Exon 5 of 11	ENSP00000504984.1	A0A7P0Z413
	TSEN54	ENST00000915433.1		c.409A>C	p.Ile137Leu	missense	Exon 5 of 11	ENSP00000585492.1

Frequencies

GnomAD3 genomes AF: 0.0969 AC: 14715 AN: 151824 Hom.: 970 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.0757

Gnomad AMR AF: 0.0753

Gnomad ASJ AF: 0.0663

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0816

Gnomad FIN AF: 0.0683

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0691

Gnomad OTH AF: 0.0938

GnomAD2 exomes AF: 0.0726 AC: 18249 AN: 251400 AF XY: 0.0727

Gnomad AFR exome AF: 0.177

Gnomad AMR exome AF: 0.0641

Gnomad ASJ exome AF: 0.0637

Gnomad EAS exome AF: 0.000544

Gnomad FIN exome AF: 0.0754

Gnomad NFE exome AF: 0.0694

Gnomad OTH exome AF: 0.0717

GnomAD4 exome AF: 0.0699 AC: 102154 AN: 1461670 Hom.: 4093 Cov.: 33 AF XY: 0.0702 AC XY: 51078 AN XY: 727118

African (AFR) AF: 0.188 AC: 6292 AN: 33478

American (AMR) AF: 0.0669 AC: 2992 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0616 AC: 1611 AN: 26136

East Asian (EAS) AF: 0.000378 AC: 15 AN: 39700

South Asian (SAS) AF: 0.0842 AC: 7262 AN: 86254

European-Finnish (FIN) AF: 0.0742 AC: 3951 AN: 53252

Middle Eastern (MID) AF: 0.105 AC: 605 AN: 5768

European-Non Finnish (NFE) AF: 0.0673 AC: 74816 AN: 1111968

Other (OTH) AF: 0.0763 AC: 4610 AN: 60390

GnomAD4 genome AF: 0.0970 AC: 14738 AN: 151942 Hom.: 975 Cov.: 32 AF XY: 0.0959 AC XY: 7118 AN XY: 74250

African (AFR) AF: 0.175 AC: 7252 AN: 41396

American (AMR) AF: 0.0752 AC: 1148 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0663 AC: 230 AN: 3470

East Asian (EAS) AF: 0.000774 AC: 4 AN: 5166

South Asian (SAS) AF: 0.0823 AC: 394 AN: 4786

European-Finnish (FIN) AF: 0.0683 AC: 723 AN: 10580

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0691 AC: 4694 AN: 67966

Other (OTH) AF: 0.0928 AC: 196 AN: 2112

Alfa AF: 0.0732 Hom.: 1464

Bravo AF: 0.102

TwinsUK AF: 0.0615 AC: 228

ALSPAC AF: 0.0672 AC: 259

ESP6500AA AF: 0.166 AC: 731

ESP6500EA AF: 0.0674 AC: 580

ExAC AF: 0.0748 AC: 9078

Asia WGS AF: 0.0430 AC: 151 AN: 3478

EpiCase AF: 0.0722

EpiControl AF: 0.0709

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Pontocerebellar hypoplasia type 2A (2)
-	-	1	Pontocerebellar hypoplasia type 4 (1)
-	-	1	Pontocerebellar hypoplasia type 5 (1)
-	-	1	Pontoneocerebellar hypoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	26
DANN	Benign	0.94
DEOGEN2	Benign	0.026	T
Eigen	Benign	0.012
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.5
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.11
Sift	Benign	0.16	T
Sift4G	Benign	0.17	T
Polyphen		0.97	D
Vest4		0.18
MPC		0.37
ClinPred		0.035	T
GERP RS		5.1
Varity_R		0.48
gMVP		0.38
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.37		Position offset: 6

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

Other links and lift over

dbSNP: rs11559205; hg19: chr17-73513677; COSMIC: COSV58689943; COSMIC: COSV58689943;