chrX-48509939-G-T

Variant names:

• chrX-48509939-G-T
• rs966935905
• NM_203475.3:c.119G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_203475.3(PORCN):​c.119G>T​(p.Arg40Leu) variant causes a missense change involving the alteration of a 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R40C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: PORCN NM_203475.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.20
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871

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.119G>T	p.Arg40Leu	missense	Exon 2 of 15	NP_982301.1	Q9H237-1
	PORCN	NM_001441333.1		c.458G>T	p.Arg153Leu	missense	Exon 2 of 14	NP_001428262.1
	PORCN	NM_001441334.1		c.458G>T	p.Arg153Leu	missense	Exon 2 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.119G>T	p.Arg40Leu	missense	Exon 2 of 15	ENSP00000322304.6	Q9H237-1
	PORCN	ENST00000355961.8	TSL:1	c.119G>T	p.Arg40Leu	missense	Exon 2 of 14	ENSP00000348233.4	Q9H237-2
	PORCN	ENST00000367574.9	TSL:1	c.119G>T	p.Arg40Leu	missense	Exon 2 of 13	ENSP00000356546.6	Q9H237-4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		8.2
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.66		Gain of catalytic residue at R40 (P = 0.0547)
MVP		0.96
MPC		2.1
ClinPred		1.0	D
GERP RS		4.5
PromoterAI		0.026	Neutral
Varity_R		0.84
gMVP		0.98
Mutation Taster		=43/57	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs966935905; hg19: chrX-48368327;