Genetic Variant SSX3:p.Glu125Lys (chrX-48350080-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_021014.4(SSX3):c.373G>A(p.Glu125Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,209 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

SSX3
NM_021014.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.433

Variant links:

Genes affected

SSX3 (HGNC:11337): (SSX family member 3) The product of this gene belongs to the family of highly homologous synovial sarcoma X (SSX) breakpoint proteins. These proteins may function as transcriptional repressors. They are also capable of eliciting spontaneous humoral and cellular immune responses in cancer patients, and are potentially useful targets in cancer vaccine-based immunotherapy. While some of the related SSX genes are involved in t(X;18)(p11.2;q11.2) translocations that are characteristically found in all synovial sarcomas, this gene does not appear to be involved in such translocations. [provided by RefSeq, Jul 2013]

SSX3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.050864488).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SSX3	NM_021014.4 link	c.373G>A	p.Glu125Lys	missense_variant	Exon 6 of 8	ENST00000298396.7	NP_066294.1	Q99909-1
SSX3	XM_011543885.3 link	c.373G>A	p.Glu125Lys	missense_variant	Exon 6 of 7		XP_011542187.1	Q99909-2A0A024R1B1
SSX3	NR_176964.1 link	n.463G>A		non_coding_transcript_exon_variant	Exon 6 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SSX3	ENST00000298396.7 link	c.373G>A	p.Glu125Lys	missense_variant	Exon 6 of 8	1	NM_021014.4	ENSP00000298396.2	Q99909-1
SSX3	ENST00000612497.1 link	c.373G>A	p.Glu125Lys	missense_variant	Exon 5 of 5	5		ENSP00000480427.1	A0A087WWQ6
SSX3	ENST00000376893.7 link	c.373G>A	p.Glu125Lys	missense_variant	Exon 6 of 8	2		ENSP00000366090.3	Q99909-2
SSX3	ENST00000376895.2 link	n.191G>A		non_coding_transcript_exon_variant	Exon 2 of 4	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000545

AC:

AN:

183469

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67899

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:

0.0000625

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1098209

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363567

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000247

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.373G>A (p.E125K) alteration is located in exon 6 (coding exon 5) of the SSX3 gene. This alteration results from a G to A substitution at nucleotide position 373, causing the glutamic acid (E) at amino acid position 125 to be replaced by a lysine (K). 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

0.094

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.45

DANN

Benign

0.26

DEOGEN2

Benign

0.018

T;.;.

FATHMM_MKL

Benign

0.0020

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Benign

0.0016

MetaRNN

Benign

0.051

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

L;L;.

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.1

N;N;.

REVEL

Benign

0.027

Sift

Benign

0.73

T;T;.

Sift4G

Benign

0.72

T;T;T

Polyphen

0.0030

B;.;.

Vest4

0.19

MutPred

0.25

Gain of ubiquitination at E125 (P = 0.0022);Gain of ubiquitination at E125 (P = 0.0022);Gain of ubiquitination at E125 (P = 0.0022);

MVP

0.061

MPC

0.023

ClinPred

0.072

GERP RS

-2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.038

gMVP

0.063

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