rs137852218

Variant names:

• chrX-48511932-C-T
• rs137852218
• NM_203475.3:c.370C>T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_203475.3(PORCN):​c.370C>T​(p.Arg124*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000709912: Functional studies of the R124X variant have shown that it impairs normal WNT3A secretions and may subsequently impact Wnt signaling (Liu et al., 2012).". Synonymous variant affecting the same amino acid position (i.e. R124R) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 21)
• Consequence: PORCN NM_203475.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.11
• Publications: 6 publications found

Genes affected

PORCN (HGNC:17652): (porcupine O-acyltransferase) This gene belongs to the evolutionarily conserved porcupine (Porc) gene family. Genes of the porcupine family encode endoplasmic reticulum proteins with multiple transmembrane domains. Porcupine proteins are involved in the processing of Wnt (wingless and int homologue) proteins. Disruption of this gene is associated with focal dermal hypoplasia, and the encoded protein has been implicated in cancer. Multiple alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Aug 2013]

PORCN Gene-Disease associations (from GenCC):

• focal dermal hypoplasia

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet
• microphthalmia, isolated, with coloboma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000709912: Functional studies of the R124X variant have shown that it impairs normal WNT3A secretions and may subsequently impact Wnt signaling (Liu et al., 2012).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-48511932-C-T is Pathogenic according to our data. Variant chrX-48511932-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203475.3. 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
	PORCN	NM_203475.3	MANE Select	c.370C>T	p.Arg124*	stop_gained	Exon 4 of 15	NP_982301.1	Q9H237-1
	PORCN	NM_001441333.1		c.709C>T	p.Arg237*	stop_gained	Exon 4 of 14	NP_001428262.1
	PORCN	NM_001441334.1		c.709C>T	p.Arg237*	stop_gained	Exon 4 of 13	NP_001428263.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PORCN	ENST00000326194.11	TSL:1 MANE Select	c.370C>T	p.Arg124*	stop_gained	Exon 4 of 15	ENSP00000322304.6	Q9H237-1
	PORCN	ENST00000355961.8	TSL:1	c.370C>T	p.Arg124*	stop_gained	Exon 4 of 14	ENSP00000348233.4	Q9H237-2
	PORCN	ENST00000367574.9	TSL:1	c.370C>T	p.Arg124*	stop_gained	Exon 4 of 13	ENSP00000356546.6	Q9H237-4

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 21

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Focal dermal hypoplasia (2)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.79	D
PhyloP100		2.1
Vest4		0.96
GERP RS		0.42
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.090		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: rs137852218; hg19: chrX-48370320; COSMIC: COSV100400509; COSMIC: COSV100400509;