Variant rs587776601 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong

The ENST00000246515.2(SLURP1):c.82del(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
ENST00000246515.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 3.99

Variant links:

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]

SLURP1 links:

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ACMG classification

Classification made for transcript

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 17 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/exons	MANE	Protein	UniProt
SLURP1	NM_020427.3 linkuse as main transcript	c.82del	p.Cys28AlafsTer5	frameshift_variant	2/3	ENST00000246515.2	NP_065160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLURP1	ENST00000246515.2 linkuse as main transcript	c.82del	p.Cys28AlafsTer5	frameshift_variant	2/3	1	NM_020427.3	ENSP00000246515	P1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

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:

AN:

249290

Hom.:

AF XY:

0.0000444

AC XY:

AN XY:

135190

show subpopulations

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:

AN:

1460552

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

726516

show subpopulations

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:

AN:

152300

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74468

show subpopulations

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.:

Bravo

AF:

0.0000604

EpiCase

AF:

0.000164

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 25, 2023	ClinVar contains an entry for this variant (Variation ID: 4599). This premature translational stop signal has been observed in individual(s) with Mal de Meleda (PMID: 11285253, 24093092). This variant is present in population databases (rs587776601, gnomAD 0.008%). 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). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2018	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. -

Acroerythrokeratoderma

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 28, 2018	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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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