rs1057518734

Variant names:

• chrX-153798074-CAG-C
• rs794729223
• NM_006280.3:c.358_359delAG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_006280.3(SSR4):​c.358_359delAG​(p.Arg120GlufsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: SSR4 NM_006280.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 7.93
• Publications: 2 publications found

Genes affected

SSR4 (HGNC:11326): (signal sequence receptor subunit 4) This gene encodes the delta subunit of the translocon-associated protein complex which is involved in translocating proteins across the endoplasmic reticulum membrane. The encoded protein is located in the Xq28 region and is arranged in a compact head-to-head manner with the isocitrate dehydrogenase 3 (NAD+) gamma gene and both genes are driven by a CpG-embedded bidirectional promoter. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Mar 2011]

SSR4 Gene-Disease associations (from GenCC):

• SSR4-congenital disorder of glycosylation

  Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-153798074-CAG-C is Pathogenic according to our data. Variant chrX-153798074-CAG-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 372144.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006280.3. 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
	SSR4	NM_006280.3	MANE Select	c.358_359delAG	p.Arg120GlufsTer2	frameshift	Exon 5 of 6	NP_006271.1	P51571
	SSR4	NM_001440795.1		c.439_440delAG	p.Arg147GlufsTer2	frameshift	Exon 6 of 7	NP_001427724.1
	SSR4	NM_001204526.2		c.391_392delAG	p.Arg131GlufsTer2	frameshift	Exon 6 of 7	NP_001191455.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SSR4	ENST00000370086.8	TSL:1 MANE Select	c.358_359delAG	p.Arg120GlufsTer2	frameshift	Exon 5 of 6	ENSP00000359103.3	P51571
	SSR4	ENST00000320857.7	TSL:2	c.358_359delAG	p.Arg120GlufsTer2	frameshift	Exon 6 of 7	ENSP00000317331.3	P51571
	SSR4	ENST00000370087.5	TSL:3	c.358_359delAG	p.Arg120GlufsTer2	frameshift	Exon 6 of 7	ENSP00000359104.1	P51571

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
3	-	-	SSR4-congenital disorder of glycosylation (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs794729223; hg19: chrX-153063529;