Genetic Variant TSPYL2:p.Arg192Trp (chrX-53083072-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_022117.4(TSPYL2):c.574C>T(p.Arg192Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,201,272 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000014 ( 0 hom. 6 hem. )

Consequence

TSPYL2
NM_022117.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.352

Variant links:

Genes affected

TSPYL2 (HGNC:24358): (TSPY like 2) This gene encodes a member of the testis-specific protein Y-encoded, TSPY-like/SET/nucleosome assembly protein-1 superfamily. The encoded protein is localized to the nucleolus where it functions in chromatin remodeling and as an inhibitor of cell-cycle progression. This protein may play a role in the suppression of tumor growth. [provided by RefSeq, Sep 2009]

TSPYL2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2150062).

BS2

High Hemizygotes in GnomAdExome4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPYL2	NM_022117.4 link	c.574C>T	p.Arg192Trp	missense_variant	Exon 1 of 7	ENST00000375442.8	NP_071400.1	Q9H2G4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSPYL2	ENST00000375442.8 link	c.574C>T	p.Arg192Trp	missense_variant	Exon 1 of 7	1	NM_022117.4	ENSP00000364591.4		Q9H2G4
TSPYL2	ENST00000578306.5 link	n.79C>T		non_coding_transcript_exon_variant	Exon 1 of 6	5		ENSP00000462635.1		J3KST2

Frequencies

GnomAD3 genomes

AF:

0.0000364

AC:

AN:

110028

Hom.:

Cov.:

AF XY:

0.0000309

AC XY:

AN XY:

32372

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000759

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000118

AC:

AN:

168963

Hom.:

AF XY:

0.00

AC XY:

AN XY:

56747

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000272

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1091244

Hom.:

Cov.:

AF XY:

0.0000168

AC XY:

AN XY:

357696

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000290

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000167

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000364

AC:

AN:

110028

Hom.:

Cov.:

AF XY:

0.0000309

AC XY:

AN XY:

32372

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000759

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.574C>T (p.R192W) alteration is located in exon 1 (coding exon 1) of the TSPYL2 gene. This alteration results from a C to T substitution at nucleotide position 574, causing the arginine (R) at amino acid position 192 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

FATHMM_MKL

Benign

0.068

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.028

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.97

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.3

REVEL

Benign

0.12

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.25

MutPred

0.22

Loss of methylation at K196 (P = 0.0827);

MVP

0.14

MPC

0.31

ClinPred

0.67

GERP RS

-2.9

Varity_R

0.26

gMVP

0.55

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over