X-48194185-C-T

Variant names:

• chrX-48194185-C-T
• rs139280367
• NM_175723.2:c.224G>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.224G>A​(p.Arg75Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000778 in 1,207,823 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 39 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 0.000027 (0 hom., 0 hem., cov: 21)
  • Exomes 𝑓: 0.000083 (0 hom. 39 hem.)
• Consequence: SSX5 NM_175723.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -5.23

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=0.020476222).
• BP6: Variant X-48194185-C-T is Benign according to our data. Variant chrX-48194185-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2257719.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 39 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SSX5	NM_175723.2	c.224G>A	p.Arg75Gln	missense_variant	Exon 4 of 8	ENST00000347757.6	NP_783729.1
SSX5	NM_021015.4	c.347G>A	p.Arg116Gln	missense_variant	Exon 5 of 9		NP_066295.3
SSX5	XM_011543949.3	c.224G>A	p.Arg75Gln	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.224G>A	p.Arg75Gln	missense_variant	Exon 4 of 8	5	NM_175723.2	ENSP00000290558.1
SSX5	ENST00000311798.5	c.347G>A	p.Arg116Gln	missense_variant	Exon 5 of 9	5		ENSP00000312415.1

Frequencies

GnomAD3 genomes AF: 0.0000273 AC: 3 AN: 110030 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 32272

Gnomad AFR AF: 0.0000331

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000787

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000709 AC: 13 AN: 183365 Hom.: 0 AF XY: 0.0000590 AC XY: 4 AN XY: 67851

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000472

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000829 AC: 91 AN: 1097744 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 39 AN XY: 363214

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000610

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000582

Gnomad4 OTH exome AF: 0.000130

GnomAD4 genome AF: 0.0000273 AC: 3 AN: 110079 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 32331

Gnomad4 AFR AF: 0.0000330

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000789

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Oct 27, 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	0.083
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.0010
DANN	Benign	0.75
DEOGEN2	Benign	0.013	T;.;T
FATHMM_MKL	Benign	0.00033	N
LIST_S2	Benign	0.66	.;T;T
M_CAP	Benign	0.00096	T
MetaRNN	Benign	0.020	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.;L
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.35	N;N;N
REVEL	Benign	0.0030
Sift	Benign	0.42	T;T;T
Sift4G	Benign	0.38	T;T;T
Polyphen		0.0070	B;B;B
Vest4		0.072
MVP		0.081
MPC		0.017
ClinPred		0.019	T
GERP RS		-3.4
Varity_R		0.022
gMVP		0.022

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs139280367; hg19: chrX-48053621; COSMIC: COSV61256036; COSMIC: COSV61256036;