X-48350080-C-T

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

1
16

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]

Genome browser will be placed here

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
SSX3NM_021014.4 linkc.373G>A p.Glu125Lys missense_variant Exon 6 of 8 ENST00000298396.7 NP_066294.1 Q99909-1
SSX3XM_011543885.3 linkc.373G>A p.Glu125Lys missense_variant Exon 6 of 7 XP_011542187.1 Q99909-2A0A024R1B1
SSX3NR_176964.1 linkn.463G>A non_coding_transcript_exon_variant Exon 6 of 9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SSX3ENST00000298396.7 linkc.373G>A p.Glu125Lys missense_variant Exon 6 of 8 1 NM_021014.4 ENSP00000298396.2 Q99909-1
SSX3ENST00000612497.1 linkc.373G>A p.Glu125Lys missense_variant Exon 5 of 5 5 ENSP00000480427.1 A0A087WWQ6
SSX3ENST00000376893.7 linkc.373G>A p.Glu125Lys missense_variant Exon 6 of 8 2 ENSP00000366090.3 Q99909-2
SSX3ENST00000376895.2 linkn.191G>A non_coding_transcript_exon_variant Exon 2 of 4 5

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD3 exomes
AF:
0.00000545
AC:
1
AN:
183469
Hom.:
0
AF XY:
0.0000147
AC XY:
1
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:
1
AN:
1098209
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
1
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.:
23

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
T
BayesDel_noAF
Benign
-0.92
CADD
Benign
0.45
DANN
Benign
0.26
DEOGEN2
Benign
0.018
T;.;.
FATHMM_MKL
Benign
0.0020
N
LIST_S2
Uncertain
0.91
D;D;D
M_CAP
Benign
0.0016
T
MetaRNN
Benign
0.051
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.2
L;L;.
PrimateAI
Benign
0.24
T
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
T
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.

Other links and lift over

dbSNP: rs1394365513; hg19: chrX-48209515; COSMIC: COSV53643662; API