8-142741224-ACA-TCT

Variant names:

• chr8-142741224-ACA-TCT
• NM_020427.3:c.229_231delTGTinsAGA
• SLURP1 p.Cys77Arg

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS1 PM1 PP2

The NM_020427.3(SLURP1):​c.229_231delTGTinsAGA​(p.Cys77Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. 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: 3.10
• Publications: 0 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, AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Ambry Genetics, Genomics England PanelApp
• 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.
• PM1: In a disulfide_bond (size 16) in uniprot entity SLUR1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_020427.3
• 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, hereditary palmoplantar keratoderma, Gamborg-Nielsen type, palmoplantar keratosis.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020427.3. 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
	SLURP1	NM_020427.3	MANE Select	c.229_231delTGTinsAGA	p.Cys77Arg	missense	N/A	NP_065160.1	P55000

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLURP1	ENST00000246515.2	TSL:1 MANE Select	c.229_231delTGTinsAGA	p.Cys77Arg	missense	N/A	ENSP00000246515.1	P55000
	ENSG00000253196	ENST00000839249.1		n.448+2740_448+2742delACAinsTCT		intron	N/A
	ENSG00000253196	ENST00000839250.1		n.295+2740_295+2742delACAinsTCT		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.1

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr8-143822642;