X-48194140-C-T

Variant names:

• chrX-48194140-C-T
• rs782483765
• NM_175723.2:c.269G>A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_175723.2(SSX5):​c.269G>A​(p.Arg90His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,097,329 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R90S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.000017 (0 hom. 8 hem.)
• Consequence: SSX5 NM_175723.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.21

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027534872).
• BP6: Variant X-48194140-C-T is Benign according to our data. Variant chrX-48194140-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3801911.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SSX5	NM_175723.2	c.269G>A	p.Arg90His	missense_variant	Exon 4 of 8	ENST00000347757.6	NP_783729.1
SSX5	NM_021015.4	c.392G>A	p.Arg131His	missense_variant	Exon 5 of 9		NP_066295.3
SSX5	XM_011543949.3	c.269G>A	p.Arg90His	missense_variant	Exon 4 of 8		XP_011542251.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SSX5	ENST00000347757.6	c.269G>A	p.Arg90His	missense_variant	Exon 4 of 8	5	NM_175723.2	ENSP00000290558.1
SSX5	ENST00000311798.5	c.392G>A	p.Arg131His	missense_variant	Exon 5 of 9	5		ENSP00000312415.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD3 exomes AF: 0.0000491 AC: 9 AN: 183302 Hom.: 0 AF XY: 0.0000884 AC XY: 6 AN XY: 67836

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.000182

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000173 AC: 19 AN: 1097329 Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 8 AN XY: 362821

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.000170

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: 0.00000713

Gnomad4 OTH exome AF: 0.0000651

GnomAD4 genome Cov.: 21

Bravo AF: 0.0000151

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 24, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-1.2
CADD	Benign	0.0010
DANN	Benign	0.84
DEOGEN2	Benign	0.0065	T;.;T
FATHMM_MKL	Benign	0.00073	N
LIST_S2	Benign	0.65	.;T;T
M_CAP	Benign	0.00043	T
MetaRNN	Benign	0.028	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.61	N;.;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.66	N;N;N
REVEL	Benign	0.0060
Sift	Benign	0.30	T;T;T
Sift4G	Benign	0.31	T;T;T
Polyphen		0.0020	B;B;B
Vest4		0.037
MutPred		0.25		Loss of loop (P = 0.1258);.;Loss of loop (P = 0.1258);
MVP		0.081
MPC		0.016
ClinPred		0.022	T
GERP RS		-3.4
Varity_R		0.025
gMVP		0.036

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: rs782483765; hg19: chrX-48053576; COSMIC: COSV61255908; COSMIC: COSV61255908;