8-142742343-A-T

Variant names:

• chr8-142742343-A-T
• rs121908318
• NM_020427.3:c.43T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS1 PM2 PP2

The NM_020427.3(SLURP1):​c.43T>A​(p.Trp15Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLURP1 NM_020427.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.100
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• mal de Meleda

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Orphanet
• hereditary palmoplantar keratoderma, Gamborg-Nielsen type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• palmoplantar keratosis

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000253196 (HGNC:58427):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PS1: Transcript NM_020427.3 (SLURP1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.59094 (below the threshold of 3.09). Trascript score misZ: 0.80412 (below the threshold of 3.09). GenCC associations: The gene is linked to mal de Meleda, palmoplantar keratosis, hereditary palmoplantar keratoderma, Gamborg-Nielsen type.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLURP1	NM_020427.3	c.43T>A	p.Trp15Arg	missense_variant	Exon 1 of 3	ENST00000246515.2	NP_065160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLURP1	ENST00000246515.2	c.43T>A	p.Trp15Arg	missense_variant	Exon 1 of 3	1	NM_020427.3	ENSP00000246515.1
ENSG00000253196	ENST00000839249.1	n.448+3859A>T		intron_variant	Intron 1 of 2
ENSG00000253196	ENST00000839250.1	n.295+3859A>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	16
DANN	Benign	0.80
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.10
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.56
Sift	Benign	0.14	T
Sift4G	Benign	0.27	T
Polyphen		0.81	P
Vest4		0.39
MutPred		0.85		Gain of methylation at W15 (P = 0.0101);
MVP		0.49
MPC		0.63
ClinPred		0.22	T
GERP RS		0.80
PromoterAI		0.0034	Neutral
Varity_R		0.19
gMVP		0.83
Mutation Taster		=34/66	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs121908318; hg19: chr8-143823761;