rs1057518735

Variant names:

• chrX-153798137-G-A
• rs1057518735
• NM_006280.3:c.417+1G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_006280.3(SSR4):​c.417+1G>A variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 24)
• Consequence: SSR4 NM_006280.3 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 6.57
• Publications: 1 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: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.12643678 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-153798137-G-A is Pathogenic according to our data. Variant chrX-153798137-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 372145.

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.417+1G>A		splice_donor intron	N/A	NP_006271.1	P51571
	SSR4	NM_001440795.1		c.498+1G>A		splice_donor intron	N/A	NP_001427724.1
	SSR4	NM_001204526.2		c.450+1G>A		splice_donor intron	N/A	NP_001191455.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SSR4	ENST00000370086.8	TSL:1 MANE Select	c.417+1G>A		splice_donor intron	N/A	ENSP00000359103.3	P51571
	SSR4	ENST00000320857.7	TSL:2	c.417+1G>A		splice_donor intron	N/A	ENSP00000317331.3	P51571
	SSR4	ENST00000370087.5	TSL:3	c.417+1G>A		splice_donor intron	N/A	ENSP00000359104.1	P51571

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	SSR4-congenital disorder of glycosylation (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	30
DANN	Uncertain	0.98
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		6.6
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.80
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1057518735; hg19: chrX-153063592;