chr8-142741226-A-G

Variant names:

• chr8-142741226-A-G
• rs121908319
• NM_020427.3:c.229T>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_020427.3(SLURP1):​c.229T>C​(p.Cys77Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,990 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SLURP1 NM_020427.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.25
• Publications: 7 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), PanelApp Australia, Genomics England PanelApp, Orphanet, Ambry Genetics
• 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a chain Secreted Ly-6/uPAR-related protein 1 (size 80) in uniprot entity SLUR1_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_020427.3
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 8-142741226-A-G is Pathogenic according to our data. Variant chr8-142741226-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 4606.Status of the report is no_assertion_criteria_provided, 0 stars.

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.229T>C	p.Cys77Arg	missense	Exon 3 of 3	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.229T>C	p.Cys77Arg	missense	Exon 3 of 3	ENSP00000246515.1	P55000
	ENSG00000253196	ENST00000839249.1		n.448+2742A>G		intron	N/A
	ENSG00000253196	ENST00000839250.1		n.295+2742A>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000409 AC: 1 AN: 244504 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457990 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725300

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.0000224 AC: 1 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5448

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111736

Other (OTH) AF: 0.00 AC: 0 AN: 60308

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Acroerythrokeratoderma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.75	D
Eigen	Benign	0.10
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.48	T
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		2.2
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-11	D
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.98		Gain of disorder (P = 0.0155)
MVP		0.85
MPC		1.2
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.95
gMVP		0.97
Mutation Taster		=76/24	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121908319; hg19: chr8-143822644;