rs11870627

Variant names:

• chr17-75524404-G-C
• rs11870627
• NM_207346.3:c.1573G>C

Your query was ambiguous. Multiple possible variants found:

• chr17-75524404-G-C
• chr17-75524404-G-A

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.1573G>C​(p.Gly525Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 1,614,046 control chromosomes in the GnomAD database, including 1,728 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (879 hom., cov: 32)
  • Exomes 𝑓: 0.0066 (849 hom.)
• Consequence: TSEN54 NM_207346.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.75
• Publications: 14 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=0.0012310445).
• BP6: Variant 17-75524404-G-C is Benign according to our data. Variant chr17-75524404-G-C is described in ClinVar as Benign. ClinVar VariationId is 137760.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN54	NM_207346.3	MANE Select	c.1573G>C	p.Gly525Arg	missense	Exon 11 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.1573G>C	p.Gly525Arg	missense	Exon 11 of 11	ENSP00000327487.6	Q7Z6J9-1
	TSEN54	ENST00000680999.1		c.1786G>C	p.Gly596Arg	missense	Exon 11 of 11	ENSP00000504984.1	A0A7P0Z413
	TSEN54	ENST00000915433.1		c.1729G>C	p.Gly577Arg	missense	Exon 11 of 11	ENSP00000585492.1

Frequencies

GnomAD3 genomes AF: 0.0602 AC: 9154 AN: 152136 Hom.: 875 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: 0.0493

GnomAD2 exomes AF: 0.0164 AC: 4122 AN: 251412 AF XY: 0.0120

Gnomad AFR exome AF: 0.214

Gnomad AMR exome AF: 0.0125

Gnomad ASJ exome AF: 0.00337

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000915

Gnomad OTH exome AF: 0.00978

GnomAD4 exome AF: 0.00656 AC: 9586 AN: 1461792 Hom.: 849 Cov.: 31 AF XY: 0.00567 AC XY: 4126 AN XY: 727192

African (AFR) AF: 0.215 AC: 7185 AN: 33478

American (AMR) AF: 0.0148 AC: 660 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00337 AC: 88 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000545 AC: 47 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53336

Middle Eastern (MID) AF: 0.0114 AC: 66 AN: 5768

European-Non Finnish (NFE) AF: 0.000622 AC: 692 AN: 1112000

Other (OTH) AF: 0.0140 AC: 848 AN: 60392

GnomAD4 genome AF: 0.0602 AC: 9172 AN: 152254 Hom.: 879 Cov.: 32 AF XY: 0.0584 AC XY: 4351 AN XY: 74448

African (AFR) AF: 0.205 AC: 8499 AN: 41522

American (AMR) AF: 0.0299 AC: 457 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

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: 68016

Other (OTH) AF: 0.0488 AC: 103 AN: 2112

Alfa AF: 0.00413 Hom.: 30

Bravo AF: 0.0690

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.202 AC: 892

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.0198 AC: 2400

Asia WGS AF: 0.0120 AC: 43 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.000889

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Pontoneocerebellar hypoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.010	T
Eigen	Benign	0.079
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.8
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.32	N
REVEL	Benign	0.089
Sift	Benign	0.17	T
Sift4G	Benign	0.28	T
Polyphen		0.0080	B
Vest4		0.048
MutPred		0.090		Gain of solvent accessibility (P = 0.0037)
MPC		0.35
ClinPred		0.0094	T
GERP RS		5.6
Varity_R		0.042
gMVP		0.20
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs11870627; hg19: chr17-73520485;