X-48511048-C-T

Variant names:

• chrX-48511048-C-T
• rs139547857
• NM_203475.3:c.137-247C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_203475.3(PORCN):​c.137-247C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 111,854 control chromosomes in the GnomAD database, including 16 homozygotes. There are 306 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.010 (16 hom., 306 hem., cov: 23)
• Consequence: PORCN NM_203475.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0280
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant X-48511048-C-T is Benign according to our data. Variant chrX-48511048-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1189911.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0103 (1153/111854) while in subpopulation AFR AF = 0.036 (1107/30755). AF 95% confidence interval is 0.0342. There are 16 homozygotes in GnomAd4. There are 306 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1153 AD,XL gene.

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.137-247C>T		intron	N/A	NP_982301.1	Q9H237-1
	PORCN	NM_001441333.1		c.476-247C>T		intron	N/A	NP_001428262.1
	PORCN	NM_001441334.1		c.476-247C>T		intron	N/A	NP_001428263.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PORCN	ENST00000326194.11	TSL:1 MANE Select	c.137-247C>T		intron	N/A	ENSP00000322304.6	Q9H237-1
	PORCN	ENST00000355961.8	TSL:1	c.137-247C>T		intron	N/A	ENSP00000348233.4	Q9H237-2
	PORCN	ENST00000367574.9	TSL:1	c.137-247C>T		intron	N/A	ENSP00000356546.6	Q9H237-4

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1154 AN: 111803 Hom.: 16 Cov.: 23

Gnomad AFR AF: 0.0361

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00313

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00424

Gnomad NFE AF: 0.0000564

Gnomad OTH AF: 0.00599

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0103 AC: 1153 AN: 111854 Hom.: 16 Cov.: 23 AF XY: 0.00899 AC XY: 306 AN XY: 34042

African (AFR) AF: 0.0360 AC: 1107 AN: 30755

American (AMR) AF: 0.00313 AC: 33 AN: 10555

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3573

South Asian (SAS) AF: 0.00 AC: 0 AN: 2681

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6066

Middle Eastern (MID) AF: 0.00465 AC: 1 AN: 215

European-Non Finnish (NFE) AF: 0.0000564 AC: 3 AN: 53146

Other (OTH) AF: 0.00591 AC: 9 AN: 1522

Alfa AF: 0.00592 Hom.: 21

Bravo AF: 0.0119

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	-0.76
CADD	Benign	7.2
DANN	Benign	0.44
PhyloP100		0.028
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs139547857; hg19: chrX-48369436;