chrX-48509898-T-C

Variant names:

• chrX-48509898-T-C
• NM_203475.3:c.78T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001441336.1(PORCN):​c.341T>C​(p.Leu114Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: PORCN NM_001441336.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.750
• Publications: 0 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_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant X-48509898-T-C is Benign according to our data. Variant chrX-48509898-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2824191.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001441336.1. 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.78T>C	p.Leu26Leu	synonymous	Exon 2 of 15	NP_982301.1	Q9H237-1
	PORCN	NM_001441336.1		c.341T>C	p.Leu114Ser	missense	Exon 3 of 14	NP_001428265.1
	PORCN	NM_001441333.1		c.417T>C	p.Leu139Leu	synonymous	Exon 2 of 14	NP_001428262.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PORCN	ENST00000326194.11	TSL:1 MANE Select	c.78T>C	p.Leu26Leu	synonymous	Exon 2 of 15	ENSP00000322304.6	Q9H237-1
	PORCN	ENST00000355961.8	TSL:1	c.78T>C	p.Leu26Leu	synonymous	Exon 2 of 14	ENSP00000348233.4	Q9H237-2
	PORCN	ENST00000367574.9	TSL:1	c.78T>C	p.Leu26Leu	synonymous	Exon 2 of 13	ENSP00000356546.6	Q9H237-4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	10
DANN	Benign	0.73
PhyloP100		0.75
PromoterAI		-0.025	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

hg19: chrX-48368286;