Genetic Variant TSPYL2:p.Cys94Arg (chrX-53082778-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_022117.4(TSPYL2):c.280T>C(p.Cys94Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000462 in 1,082,360 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000046 ( 0 hom. 0 hem. )

Consequence

TSPYL2
NM_022117.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.479

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.074413925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSPYL2	NM_022117.4 link	c.280T>C	p.Cys94Arg	missense_variant	Exon 1 of 7	ENST00000375442.8	NP_071400.1	Q9H2G4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TSPYL2	ENST00000375442.8 link	c.280T>C	p.Cys94Arg	missense_variant	Exon 1 of 7	1	NM_022117.4	ENSP00000364591.4	Q9H2G4
TSPYL2	ENST00000579390.1 link	c.168+112T>C		intron_variant	Intron 1 of 2	5		ENSP00000462287.1	J3KS33
TSPYL2	ENST00000553557.5 link	n.412T>C		non_coding_transcript_exon_variant	Exon 1 of 4	2
TSPYL2	ENST00000578306.5 link	n.-216T>C		upstream_gene_variant		5		ENSP00000462635.1	J3KST2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000136

AC:

AN:

147534

Hom.:

AF XY:

0.00

AC XY:

AN XY:

43360

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000882

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000462

AC:

AN:

1082360

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

352772

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000126

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000336

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000830

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 24, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.280T>C (p.C94R) alteration is located in exon 1 (coding exon 1) of the TSPYL2 gene. This alteration results from a T to C substitution at nucleotide position 280, causing the cysteine (C) at amino acid position 94 to be replaced by an arginine (R). 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

0.16

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.72

CADD

Benign

2.3

DANN

Benign

0.88

DEOGEN2

Benign

0.20

FATHMM_MKL

Benign

0.063

LIST_S2

Benign

0.61

M_CAP

Benign

0.016

MetaRNN

Benign

0.074

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.24

REVEL

Benign

0.046

Sift

Benign

0.042

Sift4G

Benign

0.085

Polyphen

0.40

Vest4

0.33

MutPred

0.27

Gain of disorder (P = 0.0292);

MVP

0.068

MPC

0.54

ClinPred

0.021

GERP RS

-0.74

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.28

gMVP

0.14

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