chrX-48190180-C-T

Variant names:

• chrX-48190180-C-T
• rs144094801
• NM_175723.2:c.419G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_175723.2(SSX5):​c.419G>A​(p.Arg140His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000571 in 1,208,618 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 17 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., 7 hem., cov: 22)
  • Exomes 𝑓: 0.000036 (0 hom. 10 hem.)
• Consequence: SSX5 NM_175723.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.854

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01321879).
• BS2: High Hemizygotes in GnomAd4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SSX5	NM_175723.2	c.419G>A	p.Arg140His	missense_variant	Exon 6 of 8	ENST00000347757.6	NP_783729.1
SSX5	NM_021015.4	c.542G>A	p.Arg181His	missense_variant	Exon 7 of 9		NP_066295.3
SSX5	XM_011543949.3	c.419G>A	p.Arg140His	missense_variant	Exon 6 of 8		XP_011542251.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SSX5	ENST00000347757.6	c.419G>A	p.Arg140His	missense_variant	Exon 6 of 8	5	NM_175723.2	ENSP00000290558.1
SSX5	ENST00000311798.5	c.542G>A	p.Arg181His	missense_variant	Exon 7 of 9	5		ENSP00000312415.1
SSX5	ENST00000403001.3	n.239G>A		non_coding_transcript_exon_variant	Exon 2 of 4	5

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 30 AN: 111461 Hom.: 0 Cov.: 22 AF XY: 0.000208 AC XY: 7 AN XY: 33659

Gnomad AFR AF: 0.000913

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000955

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000281

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: 0.000127 AC: 23 AN: 181180 Hom.: 0 AF XY: 0.0000304 AC XY: 2 AN XY: 65690

Gnomad AFR exome AF: 0.00131

Gnomad AMR exome AF: 0.0000369

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000221

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000247

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000355 AC: 39 AN: 1097105 Hom.: 0 Cov.: 29 AF XY: 0.0000276 AC XY: 10 AN XY: 362505

Gnomad4 AFR exome AF: 0.000759

Gnomad4 AMR exome AF: 0.0000285

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000299

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000832

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.000269 AC: 30 AN: 111513 Hom.: 0 Cov.: 22 AF XY: 0.000208 AC XY: 7 AN XY: 33721

Gnomad4 AFR AF: 0.000911

Gnomad4 AMR AF: 0.0000954

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000282

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000964 Hom.: 3

Bravo AF: 0.000310

ESP6500AA AF: 0.00130 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000132 AC: 16

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.542G>A (p.R181H) alteration is located in exon 7 (coding exon 6) of the SSX5 gene. This alteration results from a G to A substitution at nucleotide position 542, causing the arginine (R) at amino acid position 181 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	0.067
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	2.3
DANN	Benign	0.34
DEOGEN2	Benign	0.0072	T;.;T;.
FATHMM_MKL	Benign	0.0072	N
LIST_S2	Benign	0.59	.;T;T;T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.013	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N;.;N;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.25	N;N;N;N
REVEL	Benign	0.018
Sift	Benign	0.53	T;T;T;T
Sift4G	Benign	0.33	T;T;T;T
Polyphen		0.0020	B;B;B;.
Vest4		0.051
MVP		0.15
MPC		0.022
ClinPred		0.0046	T
GERP RS		0.41
Varity_R		0.048
gMVP		0.035

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: rs144094801; hg19: chrX-48049616; COSMIC: COSV61254546;