NM_207346.3:c.114T>G

Variant names:

• chr17-75516803-T-G
• rs8079373
• NM_207346.3:c.114T>G

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.114T>G​(p.His38Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,586,916 control chromosomes in the GnomAD database, including 17,494 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3419 hom., cov: 33)
  • Exomes 𝑓: 0.13 (14075 hom.)
• Consequence: TSEN54 NM_207346.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.442
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.0411305E-4).
• BP6: Variant 17-75516803-T-G is Benign according to our data. Variant chr17-75516803-T-G is described in ClinVar as Benign. ClinVar VariationId is 96671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.334 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.114T>G	p.His38Gln	missense	Exon 2 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.114T>G	p.His38Gln	missense	Exon 2 of 11	ENSP00000327487.6	Q7Z6J9-1
	TSEN54	ENST00000680999.1		c.114T>G	p.His38Gln	missense	Exon 2 of 11	ENSP00000504984.1	A0A7P0Z413
	TSEN54	ENST00000915433.1		c.114T>G	p.His38Gln	missense	Exon 2 of 11	ENSP00000585492.1

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28208 AN: 152048 Hom.: 3407 Cov.: 33

Gnomad AFR AF: 0.338

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.0204

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.191

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.179

GnomAD2 exomes AF: 0.121 AC: 25375 AN: 210344 AF XY: 0.120

Gnomad AFR exome AF: 0.317

Gnomad AMR exome AF: 0.0819

Gnomad ASJ exome AF: 0.155

Gnomad EAS exome AF: 0.0162

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.136

Gnomad OTH exome AF: 0.133

GnomAD4 exome AF: 0.134 AC: 191660 AN: 1434752 Hom.: 14075 Cov.: 51 AF XY: 0.132 AC XY: 94121 AN XY: 713076

African (AFR) AF: 0.349 AC: 11179 AN: 32062

American (AMR) AF: 0.0866 AC: 3830 AN: 44208

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 4233 AN: 25776

East Asian (EAS) AF: 0.0176 AC: 685 AN: 38940

South Asian (SAS) AF: 0.0979 AC: 8343 AN: 85262

European-Finnish (FIN) AF: 0.114 AC: 4274 AN: 37576

Middle Eastern (MID) AF: 0.155 AC: 881 AN: 5698

European-Non Finnish (NFE) AF: 0.136 AC: 150133 AN: 1105658

Other (OTH) AF: 0.136 AC: 8102 AN: 59572

GnomAD4 genome AF: 0.186 AC: 28256 AN: 152164 Hom.: 3419 Cov.: 33 AF XY: 0.182 AC XY: 13536 AN XY: 74418

African (AFR) AF: 0.338 AC: 14050 AN: 41534

American (AMR) AF: 0.133 AC: 2038 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 567 AN: 3472

East Asian (EAS) AF: 0.0201 AC: 104 AN: 5178

South Asian (SAS) AF: 0.102 AC: 491 AN: 4832

European-Finnish (FIN) AF: 0.109 AC: 1153 AN: 10582

Middle Eastern (MID) AF: 0.192 AC: 56 AN: 292

European-Non Finnish (NFE) AF: 0.138 AC: 9402 AN: 67962

Other (OTH) AF: 0.178 AC: 375 AN: 2108

Alfa AF: 0.169 Hom.: 721

Bravo AF: 0.192

TwinsUK AF: 0.132 AC: 488

ALSPAC AF: 0.129 AC: 497

ESP6500AA AF: 0.231 AC: 687

ESP6500EA AF: 0.0989 AC: 664

ExAC AF: 0.123 AC: 13916

Asia WGS AF: 0.0890 AC: 312 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)
-	-	1	Pontocerebellar hypoplasia type 4 (1)
-	-	1	Pontoneocerebellar hypoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.073
Eigen_PC	Benign	-0.034
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.00090	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.44
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.15
Sift	Benign	0.11	T
Sift4G	Benign	0.16	T
Polyphen		0.24	B
Vest4		0.097
MutPred		0.030		Gain of MoRF binding (P = 0.0899)
MPC		0.41
ClinPred		0.015	T
GERP RS		2.9
PromoterAI		0.093	Neutral
Varity_R		0.27
gMVP		0.12
Mutation Taster		=92/8	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: rs8079373; hg19: chr17-73512884; COSMIC: COSV58689806; COSMIC: COSV58689806;