rs9911502

Variant names:

• chr17-75522122-G-C
• rs9911502
• NM_207346.3:c.1041G>C

Your query was ambiguous. Multiple possible variants found:

• chr17-75522122-G-C
• chr17-75522122-G-A
• chr17-75522122-G-T

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.1041G>C​(p.Lys347Asn) variant causes a missense change. The variant allele was found at a frequency of 0.655 in 1,572,714 control chromosomes in the GnomAD database, including 350,494 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K347Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.53 (24673 hom., cov: 33)
  • Exomes 𝑓: 0.67 (325821 hom.)
• Consequence: TSEN54 NM_207346.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 3.94
• Publications: 38 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=4.242469E-6).
• BP6: Variant 17-75522122-G-C is Benign according to our data. Variant chr17-75522122-G-C is described in ClinVar as Benign. ClinVar VariationId is 160123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.691 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.1041G>C	p.Lys347Asn	missense	Exon 8 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.1041G>C	p.Lys347Asn	missense	Exon 8 of 11	ENSP00000327487.6	Q7Z6J9-1
	TSEN54	ENST00000680999.1		c.1041G>C	p.Lys347Asn	missense	Exon 8 of 11	ENSP00000504984.1	A0A7P0Z413
	TSEN54	ENST00000915433.1		c.1041G>C	p.Lys347Asn	missense	Exon 8 of 11	ENSP00000585492.1

Frequencies

GnomAD3 genomes AF: 0.528 AC: 80268 AN: 152058 Hom.: 24678 Cov.: 33

Gnomad AFR AF: 0.210

Gnomad AMI AF: 0.827

Gnomad AMR AF: 0.462

Gnomad ASJ AF: 0.599

Gnomad EAS AF: 0.461

Gnomad SAS AF: 0.647

Gnomad FIN AF: 0.707

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.696

Gnomad OTH AF: 0.543

GnomAD2 exomes AF: 0.585 AC: 111104 AN: 189948 AF XY: 0.606

Gnomad AFR exome AF: 0.193

Gnomad AMR exome AF: 0.371

Gnomad ASJ exome AF: 0.585

Gnomad EAS exome AF: 0.434

Gnomad FIN exome AF: 0.698

Gnomad NFE exome AF: 0.690

Gnomad OTH exome AF: 0.613

GnomAD4 exome AF: 0.669 AC: 950460 AN: 1420538 Hom.: 325821 Cov.: 81 AF XY: 0.672 AC XY: 471759 AN XY: 702484

African (AFR) AF: 0.184 AC: 5958 AN: 32330

American (AMR) AF: 0.383 AC: 15189 AN: 39682

Ashkenazi Jewish (ASJ) AF: 0.588 AC: 14949 AN: 25436

East Asian (EAS) AF: 0.455 AC: 16876 AN: 37106

South Asian (SAS) AF: 0.666 AC: 54262 AN: 81476

European-Finnish (FIN) AF: 0.697 AC: 34540 AN: 49528

Middle Eastern (MID) AF: 0.623 AC: 3561 AN: 5716

European-Non Finnish (NFE) AF: 0.704 AC: 768199 AN: 1090436

Other (OTH) AF: 0.628 AC: 36926 AN: 58828

GnomAD4 genome AF: 0.527 AC: 80270 AN: 152176 Hom.: 24673 Cov.: 33 AF XY: 0.529 AC XY: 39368 AN XY: 74400

African (AFR) AF: 0.210 AC: 8718 AN: 41530

American (AMR) AF: 0.462 AC: 7067 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.599 AC: 2081 AN: 3472

East Asian (EAS) AF: 0.461 AC: 2385 AN: 5178

South Asian (SAS) AF: 0.647 AC: 3126 AN: 4832

European-Finnish (FIN) AF: 0.707 AC: 7485 AN: 10592

Middle Eastern (MID) AF: 0.602 AC: 177 AN: 294

European-Non Finnish (NFE) AF: 0.696 AC: 47332 AN: 67972

Other (OTH) AF: 0.543 AC: 1146 AN: 2112

Alfa AF: 0.641 Hom.: 10545

Bravo AF: 0.491

TwinsUK AF: 0.708 AC: 2624

ALSPAC AF: 0.713 AC: 2747

ESP6500AA AF: 0.230 AC: 1008

ESP6500EA AF: 0.699 AC: 5988

ExAC AF: 0.542 AC: 63557

Asia WGS AF: 0.540 AC: 1877 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	not provided (4)
-	-	2	Pontocerebellar hypoplasia type 4 (2)
-	-	1	Pontocerebellar hypoplasia type 2A (1)
-	-	1	Pontocerebellar hypoplasia type 5 (1)
-	-	1	Pontoneocerebellar hypoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.083	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0000042	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		3.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.12
Sift	Benign	0.047	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.97	D
Vest4		0.19
MutPred		0.25		Gain of ubiquitination at K345 (P = 0.028)
MPC		0.83
ClinPred		0.032	T
GERP RS		4.5
Varity_R		0.32
gMVP		0.44
Mutation Taster		=87/13	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs9911502; hg19: chr17-73518203; COSMIC: COSV51342116; COSMIC: COSV51342116;