rs357564

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000264.5(PTCH1):c.3944C>T(p.Pro1315Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.353 in 1,612,980 control chromosomes in the GnomAD database, including 103,984 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 8748 hom., cov: 32)

Exomes 𝑓: 0.36 ( 95236 hom. )

Consequence

PTCH1
NM_000264.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17O:1

Conservation

PhyloP100: 9.54

Variant links:

Genes affected

PTCH1 (HGNC:9585): (patched 1) This gene encodes a member of the patched family of proteins and a component of the hedgehog signaling pathway. Hedgehog signaling is important in embryonic development and tumorigenesis. The encoded protein is the receptor for the secreted hedgehog ligands, which include sonic hedgehog, indian hedgehog and desert hedgehog. Following binding by one of the hedgehog ligands, the encoded protein is trafficked away from the primary cilium, relieving inhibition of the G-protein-coupled receptor smoothened, which results in activation of downstream signaling. Mutations of this gene have been associated with basal cell nevus syndrome and holoprosencephaly. [provided by RefSeq, Aug 2017]

PTCH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PTCH1. . Gene score misZ 1.6774 (greater than the threshold 3.09). Trascript score misZ 3.1343 (greater than threshold 3.09). GenCC has associacion of gene with holoprosencephaly 7, nevoid basal cell carcinoma syndrome, holoprosencephaly.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032435358).

BP6

Variant 9-95447312-G-A is Benign according to our data. Variant chr9-95447312-G-A is described in ClinVar as [Benign]. Clinvar id is 41663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95447312-G-A is described in Lovd as [Benign]. Variant chr9-95447312-G-A is described in Lovd as [Likely_benign]. Variant chr9-95447312-G-A is described in Lovd as [Pathogenic].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.546 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH1	NM_000264.5 linkuse as main transcript	c.3944C>T	p.Pro1315Leu	missense_variant	23/24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3 linkuse as main transcript	c.3941C>T	p.Pro1314Leu	missense_variant	23/24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11 linkuse as main transcript	c.3944C>T	p.Pro1315Leu	missense_variant	23/24	5	NM_000264.5	ENSP00000332353	A2	Q13635-1
PTCH1	ENST00000437951.6 linkuse as main transcript	c.3941C>T	p.Pro1314Leu	missense_variant	23/24	5	NM_001083603.3	ENSP00000389744		Q13635-2

Frequencies

GnomAD3 genomes

AF:

0.330

AC:

50147

AN:

151954

Hom.:

8752

Cov.:

show subpopulations

Gnomad AFR

AF:

0.232

Gnomad AMI

AF:

0.468

Gnomad AMR

AF:

0.387

Gnomad ASJ

AF:

0.321

Gnomad EAS

AF:

0.564

Gnomad SAS

AF:

0.472

Gnomad FIN

AF:

0.399

Gnomad MID

AF:

0.310

Gnomad NFE

AF:

0.337

Gnomad OTH

AF:

0.338

GnomAD3 exomes

AF:

0.389

AC:

95817

AN:

246178

Hom.:

19668

AF XY:

0.388

AC XY:

52207

AN XY:

134464

show subpopulations

Gnomad AFR exome

AF:

0.233

Gnomad AMR exome

AF:

0.487

Gnomad ASJ exome

AF:

0.320

Gnomad EAS exome

AF:

0.563

Gnomad SAS exome

AF:

0.447

Gnomad FIN exome

AF:

0.406

Gnomad NFE exome

AF:

0.339

Gnomad OTH exome

AF:

0.369

GnomAD4 exome

AF:

0.356

AC:

519565

AN:

1460908

Hom.:

95236

Cov.:

AF XY:

0.358

AC XY:

259922

AN XY:

726768

show subpopulations

Gnomad4 AFR exome

AF:

0.230

Gnomad4 AMR exome

AF:

0.476

Gnomad4 ASJ exome

AF:

0.315

Gnomad4 EAS exome

AF:

0.583

Gnomad4 SAS exome

AF:

0.451

Gnomad4 FIN exome

AF:

0.409

Gnomad4 NFE exome

AF:

0.338

Gnomad4 OTH exome

AF:

0.358

GnomAD4 genome

AF:

0.330

AC:

50158

AN:

152072

Hom.:

8748

Cov.:

AF XY:

0.338

AC XY:

25139

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.232

Gnomad4 AMR

AF:

0.387

Gnomad4 ASJ

AF:

0.321

Gnomad4 EAS

AF:

0.563

Gnomad4 SAS

AF:

0.472

Gnomad4 FIN

AF:

0.399

Gnomad4 NFE

AF:

0.337

Gnomad4 OTH

AF:

0.337

Alfa

AF:

0.336

Hom.:

17485

Bravo

AF:

0.326

TwinsUK

AF:

0.328

AC:

1215

ALSPAC

AF:

0.340

AC:

1309

ESP6500AA

AF:

0.239

AC:

1009

ESP6500EA

AF:

0.330

AC:

2752

ExAC

AF:

0.380

AC:

45697

Asia WGS

AF:

0.486

AC:

1685

AN:

3478

EpiCase

AF:

0.337

EpiControl

AF:

0.332

ClinVar

Significance: Benign

Submissions summary: Benign:17Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 29, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided

Benign:5

Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 29081410, 24728327, 27153395, 15888139, 22703879) -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 24, 2016	Variant summary: The PTCH1 c.3944C>T (p.Pro1315Leu) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a damaging outcome for this variant (SNPs&GO and MutationTaster not captured due to low reliability index). This variant was found in 44727/116034 control chromosomes (9126 homozygotes) at a frequency of 0.3854646, which significantly exceeds the estimated maximal expected allele frequency of a pathogenic PTCH1 variant (0.0000171), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

Gorlin syndrome

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Holoprosencephaly 7

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2014

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.38

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

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.81

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

MetaRNN

Benign

0.0032

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

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

M;.;.;.;.;.;.

MutationTaster

Benign

4.5e-11

P;P;P;P;P;P;P

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.4

N;N;N;N;N;N;N

REVEL

Uncertain

0.44

Sift

Uncertain

0.025

D;D;D;D;D;D;D

Sift4G

Uncertain

0.023

D;D;D;D;D;D;D

Polyphen

0.91

P;.;.;P;P;.;P

Vest4

0.57

MPC

0.40

ClinPred

0.027

GERP RS

4.8

Varity_R

0.21

gMVP

0.55

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

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