X-48354676-A-G

Variant names:

• chrX-48354676-A-G
• rs2061278480
• NM_021014.4:c.140T>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021014.4(SSX3):​c.140T>C​(p.Val47Ala) 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. 14/20 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. V47I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: SSX3 NM_021014.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0290

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 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=0.055313617).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SSX3	NM_021014.4	c.140T>C	p.Val47Ala	missense_variant	Exon 3 of 8	ENST00000298396.7	NP_066294.1
SSX3	XM_011543885.3	c.140T>C	p.Val47Ala	missense_variant	Exon 3 of 7		XP_011542187.1
SSX3	NR_176964.1	n.230T>C		non_coding_transcript_exon_variant	Exon 3 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SSX3	ENST00000298396.7	c.140T>C	p.Val47Ala	missense_variant	Exon 3 of 8	1	NM_021014.4	ENSP00000298396.2
SSX3	ENST00000612497.1	c.140T>C	p.Val47Ala	missense_variant	Exon 2 of 5	5		ENSP00000480427.1
SSX3	ENST00000376893.7	c.140T>C	p.Val47Ala	missense_variant	Exon 3 of 8	2		ENSP00000366090.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

Bravo AF: 0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.140T>C (p.V47A) alteration is located in exon 3 (coding exon 2) of the SSX3 gene. This alteration results from a T to C substitution at nucleotide position 140, causing the valine (V) at amino acid position 47 to be replaced by an alanine (A). 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	0.16
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.2
DANN	Benign	0.55
DEOGEN2	Benign	0.0054	T;.;.
FATHMM_MKL	Benign	0.00045	N
LIST_S2	Benign	0.040	T;T;T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.055	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.69	N;N;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.12	N;N;.
REVEL	Benign	0.012
Sift	Benign	0.65	T;T;.
Sift4G	Benign	0.59	T;T;T
Polyphen		0.0040	B;.;.
Vest4		0.093
MutPred		0.36		Loss of catalytic residue at V47 (P = 0.0056);Loss of catalytic residue at V47 (P = 0.0056);Loss of catalytic residue at V47 (P = 0.0056);
MVP		0.11
MPC		0.022
ClinPred		0.044	T
GERP RS		0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.024
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2061278480; hg19: chrX-48214111;