Genetic Variant SSX3:p.Arg90Cys (chrX-48354011-G-A) – 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_021014.4(SSX3):c.268C>T(p.Arg90Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000141 in 1,205,457 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 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 0.000091 ( 0 hom., 4 hem., cov: 21)

Exomes 𝑓: 0.0000064 ( 0 hom. 1 hem. )

Consequence

SSX3
NM_021014.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.693

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08013111).

BS2

High Hemizygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SSX3	NM_021014.4 link	c.268C>T	p.Arg90Cys	missense_variant	Exon 4 of 8	ENST00000298396.7	NP_066294.1	Q99909-1
SSX3	XM_011543885.3 link	c.268C>T	p.Arg90Cys	missense_variant	Exon 4 of 7		XP_011542187.1	Q99909-2A0A024R1B1
SSX3	NR_176964.1 link	n.358C>T		non_coding_transcript_exon_variant	Exon 4 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SSX3	ENST00000298396.7 link	c.268C>T	p.Arg90Cys	missense_variant	Exon 4 of 8	1	NM_021014.4	ENSP00000298396.2	Q99909-1
SSX3	ENST00000612497.1 link	c.268C>T	p.Arg90Cys	missense_variant	Exon 3 of 5	5		ENSP00000480427.1	A0A087WWQ6
SSX3	ENST00000376893.7 link	c.268C>T	p.Arg90Cys	missense_variant	Exon 4 of 8	2		ENSP00000366090.3	Q99909-2

Frequencies

GnomAD3 genomes

AF:

0.0000909

AC:

AN:

109998

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

32268

show subpopulations

Gnomad AFR

AF:

0.000331

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000273

AC:

AN:

183305

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

67845

show subpopulations

Gnomad AFR exome

AF:

0.000228

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000144

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:

0.00000639

AC:

AN:

1095459

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

361081

show subpopulations

Gnomad4 AFR exome

AF:

0.000190

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000332

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000909

AC:

AN:

109998

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

32268

show subpopulations

Gnomad4 AFR

AF:

0.000331

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 27, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.268C>T (p.R90C) alteration is located in exon 4 (coding exon 3) of the SSX3 gene. This alteration results from a C to T substitution at nucleotide position 268, causing the arginine (R) at amino acid position 90 to be replaced by a cysteine (C). 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

0.084

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-1.0

CADD

Benign

1.1

DANN

Benign

0.83

DEOGEN2

Benign

0.057

T;.;.

FATHMM_MKL

Benign

0.0053

LIST_S2

Benign

0.70

T;T;T

M_CAP

Benign

0.0011

MetaRNN

Benign

0.080

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.4

M;M;.

PrimateAI

Benign

0.24

PROVEAN

Uncertain

-2.9

D;D;.

REVEL

Benign

0.058

Sift

Benign

0.066

T;T;.

Sift4G

Benign

0.067

T;T;T

Polyphen

0.0010

B;.;.

Vest4

0.049

MVP

0.17

MPC

0.024

ClinPred

0.045

GERP RS

-0.62

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.22

gMVP

0.063

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.

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