rs587776601

Variant names:

• chr8-142741898-CA-C
• rs587776601
• NM_020427.3:c.82delT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_020427.3(SLURP1):​c.82delT​(p.Cys28AlafsTer5) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000663 in 1,612,852 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: SLURP1 NM_020427.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.99

Genes affected

SLURP1 (HGNC:18746): (secreted LY6/PLAUR domain containing 1) The protein encoded by this gene is a member of the Ly6/uPAR family but lacks a GPI-anchoring signal sequence. It is thought that this secreted protein contains antitumor activity. Mutations in this gene have been associated with Mal de Meleda, a rare autosomal recessive skin disorder. This gene maps to the same chromosomal region as several members of the Ly6/uPAR family of glycoprotein receptors. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
• PP5: Variant 8-142741898-CA-C is Pathogenic according to our data. Variant chr8-142741898-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 4599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-142741898-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLURP1	NM_020427.3	c.82delT	p.Cys28AlafsTer5	frameshift_variant	Exon 2 of 3	ENST00000246515.2	NP_065160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLURP1	ENST00000246515.2	c.82delT	p.Cys28AlafsTer5	frameshift_variant	Exon 2 of 3	1	NM_020427.3	ENSP00000246515.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000321 AC: 8 AN: 249290 Hom.: 0 AF XY: 0.0000444 AC XY: 6 AN XY: 135190

Gnomad AFR exome AF: 0.0000620

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: 0.0000533

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000664 AC: 97 AN: 1460552 Hom.: 0 Cov.: 32 AF XY: 0.0000619 AC XY: 45 AN XY: 726516

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000845

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152300 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74468

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000604

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Acroerythrokeratoderma Pathogenic:3

Mar 28, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SLURP1 c.82delT (p.Cys28AlafsTer5) variant results in a frameshift and is predicted to result in premature termination of the protein. Across a selection of the literature, the p.Cys28AlafsTer5 variant has been reported in a homozygous state in a total of 15 individuals affected with mal de Meleda from eight families (Charfeddine et al. 2003; Ward et al. 2003; Bchetnia et al. 2013; Bergqvist et al. 2018). Both Charfeddine et al. (2003) and Ward et al. (2003) demonstrated that the parents of the affected individuals carried the variant in a heterozygous state. Additionally, Fischer et al. (2001) identified the p.Cys28AlafsTer5 variant in a homozygous state in an unknown number of affected individuals from 15 families. Two female obligate carriers of the p.Cys28AlafsTer5 variant were shown to have attenuated signs of skin disease (Mokni et al. 2004). Favre et al. (2007) demonstrated that the sweat of one individual with the p.Cys28AlafsTer5 variant showed an absence of SLURP1. The p.Cys28AlafsTer5 variant was absent from 200 Palestinian controls, but is reported at a frequency of 0.000079 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence and potential impact of frameshift variants, the p.Cys28AlafsTer5 variant is classified as pathogenic for mal de Meleda. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Jul 20, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:2

Jul 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is present in population databases (rs587776601, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with Mal de Meleda (PMID: 11285253, 24093092). ClinVar contains an entry for this variant (Variation ID: 4599). For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Cys28Alafs*5) in the SLURP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLURP1 are known to be pathogenic (PMID: 11285253, 19692209). -

May 03, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.82delT pathogenic variant in the SLURP1 gene has been reported previously in the homozygous state in multiple unrelated individuals with Mal de Maleda (Fischer et al., 2001; Charfeddine et al., 2003). The c.82delT variant causes a frameshift starting with codon Cysteine 28, changes this amino acid to an Alanine residue, and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Cys28AlafsX5. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.82delT variant is observed in 10/126,090 (0.008%) alleles from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). We interpret c.82delT as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs587776601; hg19: chr8-143823316;