17-75516572-G-T

Variant names:

• chr17-75516572-G-T
• rs7216673
• NM_207346.3:c.12G>T

Variant summary

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

The ENST00000333213.11(TSEN54):​c.12G>T​(p.Glu4Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.682 in 1,149,816 control chromosomes in the GnomAD database, including 271,174 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E4E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.59 (27373 hom., cov: 32)
  • Exomes 𝑓: 0.70 (243801 hom.)
• Consequence: TSEN54 ENST00000333213.11 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -2.89
• Publications: 16 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: Computational evidence support a benign effect (MetaRNN=4.9241294E-6).
• BP6: Variant 17-75516572-G-T is Benign according to our data. Variant chr17-75516572-G-T is described in ClinVar as Benign. ClinVar VariationId is 96673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.692 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000333213.11. 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.12G>T	p.Glu4Asp	missense	Exon 1 of 11	NP_997229.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN54	ENST00000333213.11	TSL:1 MANE Select	c.12G>T	p.Glu4Asp	missense	Exon 1 of 11	ENSP00000327487.6
	TSEN54	ENST00000680999.1		c.12G>T	p.Glu4Asp	missense	Exon 1 of 11	ENSP00000504984.1
	TSEN54	ENST00000545228.3	TSL:5	c.12G>T	p.Glu4Asp	missense	Exon 1 of 11	ENSP00000438169.3

Frequencies

GnomAD3 genomes AF: 0.592 AC: 88376 AN: 149396 Hom.: 27379 Cov.: 32

Gnomad AFR AF: 0.423

Gnomad AMI AF: 0.828

Gnomad AMR AF: 0.487

Gnomad ASJ AF: 0.603

Gnomad EAS AF: 0.520

Gnomad SAS AF: 0.689

Gnomad FIN AF: 0.695

Gnomad MID AF: 0.602

Gnomad NFE AF: 0.698

Gnomad OTH AF: 0.596

GnomAD2 exomes AF: 0.760 AC: 79 AN: 104 AF XY: 0.719

Gnomad NFE exome AF: 0.760

GnomAD4 exome AF: 0.696 AC: 695858 AN: 1000312 Hom.: 243801 Cov.: 57 AF XY: 0.697 AC XY: 328210 AN XY: 470990

African (AFR) AF: 0.398 AC: 7924 AN: 19894

American (AMR) AF: 0.454 AC: 2586 AN: 5690

Ashkenazi Jewish (ASJ) AF: 0.602 AC: 6550 AN: 10874

East Asian (EAS) AF: 0.513 AC: 9215 AN: 17958

South Asian (SAS) AF: 0.710 AC: 13376 AN: 18850

European-Finnish (FIN) AF: 0.702 AC: 11734 AN: 16706

Middle Eastern (MID) AF: 0.619 AC: 1532 AN: 2474

European-Non Finnish (NFE) AF: 0.710 AC: 618080 AN: 870090

Other (OTH) AF: 0.658 AC: 24861 AN: 37776

GnomAD4 genome AF: 0.591 AC: 88389 AN: 149504 Hom.: 27373 Cov.: 32 AF XY: 0.590 AC XY: 43055 AN XY: 72966

African (AFR) AF: 0.423 AC: 17399 AN: 41152

American (AMR) AF: 0.487 AC: 7320 AN: 15046

Ashkenazi Jewish (ASJ) AF: 0.603 AC: 2072 AN: 3434

East Asian (EAS) AF: 0.520 AC: 2665 AN: 5124

South Asian (SAS) AF: 0.688 AC: 3316 AN: 4818

European-Finnish (FIN) AF: 0.695 AC: 6691 AN: 9630

Middle Eastern (MID) AF: 0.610 AC: 178 AN: 292

European-Non Finnish (NFE) AF: 0.698 AC: 46760 AN: 67024

Other (OTH) AF: 0.595 AC: 1233 AN: 2072

Alfa AF: 0.562 Hom.: 2148

Bravo AF: 0.566

ExAC AF: 0.259 AC: 181

Asia WGS AF: 0.599 AC: 1827 AN: 3054

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	-	1	Pontocerebellar hypoplasia type 2A (1)
-	-	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	0.083
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.043
DANN	Benign	0.80
DEOGEN2	Benign	0.0099	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0064	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0000049	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		-2.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.059
Sift	Benign	0.30	T
Sift4G	Benign	0.13	T
Polyphen		0.0	B
Vest4		0.022
MutPred		0.15		Loss of glycosylation at P3 (P = 0.0618)
MPC		0.23
ClinPred		0.087	T
GERP RS		-8.9
PromoterAI		0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.037
gMVP		0.14
Mutation Taster		=98/2	polymorphism (auto)

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: rs7216673; hg19: chr17-73512653; COSMIC: COSV58690968; COSMIC: COSV58690968;