chrX-48511932-C-T

Position:

• chrX-48511932-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_203475.3(PORCN):​c.370C>T​(p.Arg124Ter) 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 (★★). 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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 id is 10702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-48511932-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PORCN	NM_203475.3	c.370C>T	p.Arg124Ter	stop_gained	4/15	ENST00000326194.11	NP_982301.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PORCN	ENST00000326194.11	c.370C>T	p.Arg124Ter	stop_gained	4/15	1	NM_203475.3	ENSP00000322304	A1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 16, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 10702). This premature translational stop signal has been observed in individual(s) with focal dermal hypoplasia (PMID: 17546030). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg124*) in the PORCN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PORCN are known to be pathogenic (PMID: 17546030, 19309688). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2018	The R124X nonsense variant in the PORCN gene has been reported previously in association with Goltz syndrome including as a de novo occurrence (Grzeschik et al., 2007; Bornholdt et al., 2009; Lombardi et al., 2011; Wang et al., 2007). The variant is not observed in large population cohorts (Lek et al., 2016). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Functional studies of the R124X variant have shown that it impairs normal WNT3A secretions and may subsequently impact Wnt signaling (Liu et al., 2012). -

Focal dermal hypoplasia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 16, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2007	- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
Vest4		0.96
GERP RS		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs137852218; hg19: chrX-48370320; COSMIC: COSV100400509; COSMIC: COSV100400509;