rs587776737

Variant names:

• chrX-48515922-G-GTCCCTGGCTTTTA
• rs587776737
• NM_203475.3:c.1059_1071dupCCTGGCTTTTATC

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_203475.3(PORCN):​c.1059_1071dupCCTGGCTTTTATC​(p.Thr358ProfsTer65) variant causes a frameshift 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 INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: PORCN NM_203475.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.46
• Publications: 3 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: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant X-48515922-G-GTCCCTGGCTTTTA is Pathogenic according to our data. Variant chrX-48515922-G-GTCCCTGGCTTTTA is described in ClinVar as Pathogenic. ClinVar VariationId is 10700.Status of the report is no_assertion_criteria_provided, 0 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.1059_1071dupCCTGGCTTTTATC	p.Thr358ProfsTer65	frameshift	Exon 12 of 15	NP_982301.1	Q9H237-1
	PORCN	NM_001441333.1		c.1383_1395dupCCTGGCTTTTATC	p.Thr466ProfsTer65	frameshift	Exon 11 of 14	NP_001428262.1
	PORCN	NM_001441334.1		c.1365_1377dupCCTGGCTTTTATC	p.Thr460ProfsTer65	frameshift	Exon 10 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.1059_1071dupCCTGGCTTTTATC	p.Thr358ProfsTer65	frameshift	Exon 12 of 15	ENSP00000322304.6	Q9H237-1
	PORCN	ENST00000355961.8	TSL:1	c.1044_1056dupCCTGGCTTTTATC	p.Thr353ProfsTer65	frameshift	Exon 11 of 14	ENSP00000348233.4	Q9H237-2
	PORCN	ENST00000367574.9	TSL:1	c.1026_1038dupCCTGGCTTTTATC	p.Thr347ProfsTer65	frameshift	Exon 10 of 13	ENSP00000356546.6	Q9H237-4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Focal dermal hypoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs587776737; hg19: chrX-48374310;