X-48352108-A-C

Variant names:

• chrX-48352108-A-C
• rs2061265847
• NM_021014.4:c.322T>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021014.4(SSX3):​c.322T>G​(p.Phe108Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F108Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: SSX3 NM_021014.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.19

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]

ACMG classification

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=0.08290669).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SSX3	NM_021014.4	c.322T>G	p.Phe108Val	missense_variant	Exon 5 of 8	ENST00000298396.7	NP_066294.1
SSX3	XM_011543885.3	c.322T>G	p.Phe108Val	missense_variant	Exon 5 of 7		XP_011542187.1
SSX3	NR_176964.1	n.412T>G		non_coding_transcript_exon_variant	Exon 5 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SSX3	ENST00000298396.7	c.322T>G	p.Phe108Val	missense_variant	Exon 5 of 8	1	NM_021014.4	ENSP00000298396.2
SSX3	ENST00000612497.1	c.322T>G	p.Phe108Val	missense_variant	Exon 4 of 5	5		ENSP00000480427.1
SSX3	ENST00000376893.7	c.322T>G	p.Phe108Val	missense_variant	Exon 5 of 8	2		ENSP00000366090.3
SSX3	ENST00000376895.2	n.140T>G		non_coding_transcript_exon_variant	Exon 1 of 4	5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.322T>G (p.F108V) alteration is located in exon 5 (coding exon 4) of the SSX3 gene. This alteration results from a T to G substitution at nucleotide position 322, causing the phenylalanine (F) at amino acid position 108 to be replaced by a valine (V). 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	0.12
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.061
DANN	Benign	0.44
DEOGEN2	Benign	0.024	T;.;.
FATHMM_MKL	Benign	0.0035	N
LIST_S2	Benign	0.57	T;T;T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.083	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.7	N;N;.
REVEL	Benign	0.029
Sift	Benign	0.46	T;T;.
Sift4G	Benign	0.18	T;T;T
Polyphen		0.011	B;.;.
Vest4		0.099
MutPred		0.33		Gain of catalytic residue at F108 (P = 0.0155);Gain of catalytic residue at F108 (P = 0.0155);Gain of catalytic residue at F108 (P = 0.0155);
MVP		0.27
MPC		0.023
ClinPred		0.20	T
GERP RS		0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.059
gMVP		0.055

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

Other links and lift over

dbSNP: rs2061265847; hg19: chrX-48211543;