Genetic Variant PORCN:p.Val57Met (chrX-48511327-G-A) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4BP6_ModerateBS2

The NM_203475.3(PORCN):c.169G>A(p.Val57Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000191 in 1,206,054 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 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 0.000027 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000018 ( 0 hom. 5 hem. )

Consequence

PORCN
NM_203475.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.63

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.35544154).

BP6

Variant X-48511327-G-A is Benign according to our data. Variant chrX-48511327-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1663393.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PORCN	NM_203475.3 link	c.169G>A	p.Val57Met	missense_variant	Exon 3 of 15	ENST00000326194.11	NP_982301.1	Q9H237-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PORCN	ENST00000326194.11 link	c.169G>A	p.Val57Met	missense_variant	Exon 3 of 15	1	NM_203475.3	ENSP00000322304.6		Q9H237-1

Frequencies

GnomAD3 genomes

AF:

0.0000273

AC:

AN:

109881

Hom.:

Cov.:

AF XY:

0.0000308

AC XY:

AN XY:

32503

show subpopulations

Gnomad AFR

AF:

0.0000994

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000436

AC:

AN:

183423

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

67857

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.000109

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000524

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000244

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000182

AC:

AN:

1096173

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

361827

show subpopulations

Gnomad4 AFR exome

AF:

0.000114

Gnomad4 AMR exome

AF:

0.000142

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000119

Gnomad4 OTH exome

AF:

0.0000218

GnomAD4 genome

AF:

0.0000273

AC:

AN:

109881

Hom.:

Cov.:

AF XY:

0.0000308

AC XY:

AN XY:

32503

show subpopulations

Gnomad4 AFR

AF:

0.0000994

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Oct 24, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

0.0096

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.49

.;.;.;.;T;.;.

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.96

.;.;D;D;D;D;D

M_CAP

Pathogenic

0.80

MetaRNN

Benign

0.36

T;T;T;T;T;T;T

MetaSVM

Pathogenic

0.83

MutationAssessor

Benign

1.4

L;L;.;L;L;L;L

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.63

N;N;N;N;N;.;N

REVEL

Uncertain

0.38

Sift

Benign

0.37

T;T;T;T;T;.;T

Sift4G

Benign

0.26

T;T;D;T;T;T;T

Polyphen

0.29

B;B;D;B;P;B;B

Vest4

0.17

MutPred

0.35

Loss of catalytic residue at V57 (P = 0.0672);Loss of catalytic residue at V57 (P = 0.0672);Loss of catalytic residue at V57 (P = 0.0672);Loss of catalytic residue at V57 (P = 0.0672);Loss of catalytic residue at V57 (P = 0.0672);Loss of catalytic residue at V57 (P = 0.0672);Loss of catalytic residue at V57 (P = 0.0672);

MVP

0.86

MPC

0.80

ClinPred

0.044

GERP RS

4.7

Varity_R

0.14

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over