8-142741243-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_ModeratePM1PM5PP3_Strong

The NM_020427.3(SLURP1):​c.212G>A​(p.Arg71His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000871 in 1,607,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R71C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

SLURP1
NM_020427.3 missense

Scores

2
8
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.192
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PS1
Transcript NM_020427.3 (SLURP1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM1
In a chain Secreted Ly-6/uPAR-related protein 1 (size 80) in uniprot entity SLUR1_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) in NM_020427.3
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.943

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLURP1NM_020427.3 linkc.212G>A p.Arg71His missense_variant Exon 3 of 3 ENST00000246515.2 NP_065160.1 P55000

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLURP1ENST00000246515.2 linkc.212G>A p.Arg71His missense_variant Exon 3 of 3 1 NM_020427.3 ENSP00000246515.1 P55000

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152124
Hom.:
0
Cov.:
33
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000839
AC:
2
AN:
238284
Hom.:
0
AF XY:
0.00000771
AC XY:
1
AN XY:
129700
show subpopulations
Gnomad AFR exome
AF:
0.00
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:
0.0000187
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000893
AC:
13
AN:
1455242
Hom.:
0
Cov.:
31
AF XY:
0.00000829
AC XY:
6
AN XY:
723756
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000117
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000990
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152124
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74304
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Sep 10, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 71 of the SLURP1 protein (p.Arg71His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with clinical features of autosomal recessive SLURP1-related conditions (PMID: 17008884). This variant is also known as c.238G>A. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SLURP1 function (PMID: 33741389). This variant disrupts the p.Arg71 amino acid residue in SLURP1. Other variant(s) that disrupt this residue have been observed in individuals with SLURP1-related conditions (PMID: 19120323, 37393290), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.33
BayesDel_addAF
Uncertain
0.069
T
BayesDel_noAF
Benign
-0.14
CADD
Benign
23
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.61
D
Eigen
Benign
-0.020
Eigen_PC
Benign
-0.20
FATHMM_MKL
Benign
0.11
N
LIST_S2
Benign
0.68
T
M_CAP
Uncertain
0.10
D
MetaRNN
Pathogenic
0.94
D
MetaSVM
Benign
-0.54
T
MutationAssessor
Uncertain
2.6
M
PrimateAI
Benign
0.36
T
PROVEAN
Uncertain
-3.3
D
REVEL
Uncertain
0.54
Sift
Uncertain
0.0070
D
Sift4G
Uncertain
0.032
D
Polyphen
1.0
D
Vest4
0.66
MutPred
0.83
Gain of glycosylation at S76 (P = 0.0706);
MVP
0.78
MPC
0.99
ClinPred
0.94
D
GERP RS
1.8
Varity_R
0.65
gMVP
0.83

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.12
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.

Other links and lift over

dbSNP: rs1448017161; hg19: chr8-143822661; API