X-48194169-C-G

Variant names:

• chrX-48194169-C-G
• rs782405587
• NM_175723.2:c.240G>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_175723.2(SSX5):​c.240G>C​(p.Gln80His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,208,140 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q80P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., 5 hem., cov: 21)
  • Exomes 𝑓: 0.000012 (0 hom. 3 hem.)
• Consequence: SSX5 NM_175723.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.14
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03426498).
• BS2: High Hemizygotes in GnomAd4 at 5 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175723.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SSX5	NM_175723.2	MANE Select	c.240G>C	p.Gln80His	missense	Exon 4 of 8	NP_783729.1	O60225-1
	SSX5	NM_021015.4		c.363G>C	p.Gln121His	missense	Exon 5 of 9	NP_066295.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SSX5	ENST00000347757.6	TSL:5 MANE Select	c.240G>C	p.Gln80His	missense	Exon 4 of 8	ENSP00000290558.1	O60225-1
	SSX5	ENST00000311798.5	TSL:5	c.363G>C	p.Gln121His	missense	Exon 5 of 9	ENSP00000312415.1	O60225-2

Frequencies

GnomAD3 genomes AF: 0.000154 AC: 17 AN: 110289 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.000528

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000677

GnomAD2 exomes AF: 0.0000491 AC: 9 AN: 183371 AF XY: 0.0000147

Gnomad AFR exome AF: 0.000684

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.0000118 AC: 13 AN: 1097851 Hom.: 0 Cov.: 32 AF XY: 0.00000826 AC XY: 3 AN XY: 363315

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000493 AC: 13 AN: 26389

American (AMR) AF: 0.00 AC: 0 AN: 35198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19375

East Asian (EAS) AF: 0.00 AC: 0 AN: 30197

South Asian (SAS) AF: 0.00 AC: 0 AN: 54128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40513

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841851

Other (OTH) AF: 0.00 AC: 0 AN: 46068

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000126982), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000154 AC: 17 AN: 110289 Hom.: 0 Cov.: 21 AF XY: 0.000154 AC XY: 5 AN XY: 32493

African (AFR) AF: 0.000528 AC: 16 AN: 30280

American (AMR) AF: 0.00 AC: 0 AN: 10208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2630

East Asian (EAS) AF: 0.00 AC: 0 AN: 3504

South Asian (SAS) AF: 0.00 AC: 0 AN: 2551

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5802

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52916

Other (OTH) AF: 0.000677 AC: 1 AN: 1477

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000193

ExAC AF: 0.0000577 AC: 7

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.035
DANN	Benign	0.53
DEOGEN2	Benign	0.048	T
FATHMM_MKL	Benign	0.0020	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.00062	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		-2.1
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.016
Sift	Benign	0.11	T
Sift4G	Benign	0.092	T
Polyphen		0.011	B
Vest4		0.12
MutPred		0.21		Loss of disorder (P = 0.125)
MVP		0.072
MPC		0.016
ClinPred		0.038	T
GERP RS		-3.4
Varity_R		0.068
gMVP		0.051
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs782405587; hg19: chrX-48053605;