X-48350117-C-T

Variant summary

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

The NM_021014.4(SSX3):​c.336G>A​(p.Met112Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000024 in 1,209,751 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 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 (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 22)
Exomes 𝑓: 0.000025 ( 0 hom. 8 hem. )

Consequence

SSX3
NM_021014.4 missense

Scores

2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.324
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 -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.11150673).
BS2
High Hemizygotes in GnomAdExome4 at 8 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SSX3NM_021014.4 linkc.336G>A p.Met112Ile missense_variant Exon 6 of 8 ENST00000298396.7 NP_066294.1 Q99909-1
SSX3XM_011543885.3 linkc.336G>A p.Met112Ile missense_variant Exon 6 of 7 XP_011542187.1 Q99909-2A0A024R1B1
SSX3NR_176964.1 linkn.426G>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.336G>A p.Met112Ile missense_variant Exon 6 of 8 1 NM_021014.4 ENSP00000298396.2 Q99909-1
SSX3ENST00000612497.1 linkc.336G>A p.Met112Ile missense_variant Exon 5 of 5 5 ENSP00000480427.1 A0A087WWQ6
SSX3ENST00000376893.7 linkc.336G>A p.Met112Ile missense_variant Exon 6 of 8 2 ENSP00000366090.3 Q99909-2
SSX3ENST00000376895.2 linkn.154G>A non_coding_transcript_exon_variant Exon 2 of 4 5

Frequencies

GnomAD3 genomes
AF:
0.0000179
AC:
2
AN:
111721
Hom.:
0
Cov.:
22
AF XY:
0.0000295
AC XY:
1
AN XY:
33897
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000957
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:
0.0000188
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000273
AC:
5
AN:
183309
Hom.:
0
AF XY:
0.0000295
AC XY:
2
AN XY:
67749
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:
0.0000525
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000366
Gnomad OTH exome
AF:
0.000221
GnomAD4 exome
AF:
0.0000246
AC:
27
AN:
1098030
Hom.:
0
Cov.:
32
AF XY:
0.0000220
AC XY:
8
AN XY:
363394
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:
0.0000369
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000261
Gnomad4 OTH exome
AF:
0.0000651
GnomAD4 genome
AF:
0.0000179
AC:
2
AN:
111721
Hom.:
0
Cov.:
22
AF XY:
0.0000295
AC XY:
1
AN XY:
33897
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000957
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000188
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000868
Hom.:
1
Bravo
AF:
0.0000151
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.0000545
EpiControl
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
Dec 08, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.336G>A (p.M112I) 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 336, causing the methionine (M) at amino acid position 112 to be replaced by an isoleucine (I). 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
0.27
BayesDel_addAF
Benign
-0.50
T
BayesDel_noAF
Benign
-0.81
CADD
Benign
8.2
DANN
Benign
0.61
DEOGEN2
Benign
0.052
T;.;.
FATHMM_MKL
Benign
0.0099
N
LIST_S2
Benign
0.76
T;T;T
M_CAP
Benign
0.0023
T
MetaRNN
Benign
0.11
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.2
M;M;.
PrimateAI
Benign
0.37
T
PROVEAN
Uncertain
-2.6
D;D;.
REVEL
Benign
0.039
Sift
Benign
0.14
T;T;.
Sift4G
Benign
0.15
T;T;D
Polyphen
0.0010
B;.;.
Vest4
0.19
MutPred
0.31
Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);
MVP
0.21
MPC
0.023
ClinPred
0.26
T
GERP RS
1.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.19
gMVP
0.082

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs782608341; hg19: chrX-48209552; COSMIC: COSV53643624; API