X-48192272-G-T

Variant names:

• chrX-48192272-G-T
• rs1556924919
• NM_175723.2:c.290C>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_175723.2(SSX5):​c.290C>A​(p.Pro97His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000273 in 1,097,691 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 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: not found (cov: 24)
  • Exomes 𝑓: 0.0000027 (0 hom. 2 hem.)
• Consequence: SSX5 NM_175723.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.09

Genes affected

SSX5 (HGNC:11339): (SSX family member 5) 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. Two transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13207847).
• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SSX5	NM_175723.2	c.290C>A	p.Pro97His	missense_variant	Exon 5 of 8	ENST00000347757.6	NP_783729.1
SSX5	NM_021015.4	c.413C>A	p.Pro138His	missense_variant	Exon 6 of 9		NP_066295.3
SSX5	XM_011543949.3	c.290C>A	p.Pro97His	missense_variant	Exon 5 of 8		XP_011542251.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SSX5	ENST00000347757.6	c.290C>A	p.Pro97His	missense_variant	Exon 5 of 8	5	NM_175723.2	ENSP00000290558.1
SSX5	ENST00000311798.5	c.413C>A	p.Pro138His	missense_variant	Exon 6 of 9	5		ENSP00000312415.1
SSX5	ENST00000403001.3	n.110C>A		non_coding_transcript_exon_variant	Exon 1 of 4	5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.00000546 AC: 1 AN: 183286 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67852

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: 0.0000524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1097691 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 2 AN XY: 363225

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: 0.0000554

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.413C>A (p.P138H) alteration is located in exon 6 (coding exon 5) of the SSX5 gene. This alteration results from a C to A substitution at nucleotide position 413, causing the proline (P) at amino acid position 138 to be replaced by a histidine (H). 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	0.13
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.022
DANN	Benign	0.77
DEOGEN2	Benign	0.11	T;.;T;.
FATHMM_MKL	Benign	0.0069	N
LIST_S2	Benign	0.64	.;T;T;T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.5	M;.;M;.
PrimateAI	Benign	0.25	T
PROVEAN	Pathogenic	-4.9	D;D;D;D
REVEL	Benign	0.033
Sift	Benign	0.052	T;D;T;D
Sift4G	Uncertain	0.059	T;T;T;D
Polyphen		0.0080	B;D;B;.
Vest4		0.12
MutPred		0.23		Gain of catalytic residue at P97 (P = 0.054);.;Gain of catalytic residue at P97 (P = 0.054);.;
MVP		0.36
MPC		0.12
ClinPred		0.096	T
GERP RS		-1.7
Varity_R		0.18
gMVP		0.044

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: rs1556924919; hg19: chrX-48051708;