X-48192246-C-T

Variant names:

• chrX-48192246-C-T
• rs782656154
• NM_175723.2:c.316G>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.316G>A​(p.Gly106Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,209,655 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 61 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 (★).

• Frequency:
  • Genomes: 𝑓 0.00069 (0 hom., 21 hem., cov: 23)
  • Exomes 𝑓: 0.000087 (0 hom. 40 hem.)
• Consequence: SSX5 NM_175723.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.96

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=0.009957939).
• BP6: Variant X-48192246-C-T is Benign according to our data. Variant chrX-48192246-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2207502.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 21 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SSX5	NM_175723.2	c.316G>A	p.Gly106Arg	missense_variant	Exon 5 of 8	ENST00000347757.6	NP_783729.1
SSX5	NM_021015.4	c.439G>A	p.Gly147Arg	missense_variant	Exon 6 of 9		NP_066295.3
SSX5	XM_011543949.3	c.316G>A	p.Gly106Arg	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.316G>A	p.Gly106Arg	missense_variant	Exon 5 of 8	5	NM_175723.2	ENSP00000290558.1
SSX5	ENST00000311798.5	c.439G>A	p.Gly147Arg	missense_variant	Exon 6 of 9	5		ENSP00000312415.1
SSX5	ENST00000403001.3	n.136G>A		non_coding_transcript_exon_variant	Exon 1 of 4	5

Frequencies

GnomAD3 genomes AF: 0.000680 AC: 76 AN: 111821 Hom.: 0 Cov.: 23 AF XY: 0.000588 AC XY: 20 AN XY: 33995

Gnomad AFR AF: 0.00231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000280

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00133

GnomAD3 exomes AF: 0.0000764 AC: 14 AN: 183249 Hom.: 0 AF XY: 0.0000590 AC XY: 4 AN XY: 67853

Gnomad AFR exome AF: 0.00107

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000874 AC: 96 AN: 1097780 Hom.: 0 Cov.: 31 AF XY: 0.000110 AC XY: 40 AN XY: 363320

Gnomad4 AFR exome AF: 0.00216

Gnomad4 AMR exome AF: 0.0000568

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.0000190

Gnomad4 OTH exome AF: 0.000217

GnomAD4 genome AF: 0.000688 AC: 77 AN: 111875 Hom.: 0 Cov.: 23 AF XY: 0.000617 AC XY: 21 AN XY: 34059

Gnomad4 AFR AF: 0.00234

Gnomad4 AMR AF: 0.000190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000281

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00131

Alfa AF: 0.000478 Hom.: 4

Bravo AF: 0.000824

ExAC AF: 0.000214 AC: 26

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jul 14, 2021

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	0.12
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.0030
DANN	Benign	0.67
DEOGEN2	Benign	0.0025	T;.;T;.
FATHMM_MKL	Benign	0.00055	N
LIST_S2	Benign	0.75	.;T;T;T
M_CAP	Benign	0.00091	T
MetaRNN	Benign	0.010	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.34	N;.;N;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.57	N;N;N;N
REVEL	Benign	0.0020
Sift	Benign	0.95	T;T;T;T
Sift4G	Benign	0.46	T;T;T;T
Polyphen		0.0010	B;B;B;.
Vest4		0.039
MutPred		0.24		Gain of MoRF binding (P = 0.0122);.;Gain of MoRF binding (P = 0.0122);.;
MVP		0.13
MPC		0.016
ClinPred		0.010	T
GERP RS		-1.9
Varity_R		0.056
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: rs782656154; hg19: chrX-48051682; COSMIC: COSV61255763; COSMIC: COSV61255763;