NM_000264.5:c.3944C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1315S) has been classified as Likely 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:18O:1

Conservation

PhyloP100: 9.54

Publications

118 publications found

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 Gene-Disease associations (from GenCC):

basal cell nevus syndrome 1
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
holoprosencephaly 7
Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
nevoid basal cell carcinoma syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
holoprosencephaly
Inheritance: AD Classification: LIMITED Submitted by: Illumina

PTCH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

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 VariationId is 41663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
PTCH1	NM_000264.5 link	c.3944C>T	p.Pro1315Leu	missense_variant	Exon 23 of 24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3 link	c.3941C>T	p.Pro1314Leu	missense_variant	Exon 23 of 24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11 link	c.3944C>T	p.Pro1315Leu	missense_variant	Exon 23 of 24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6 link	c.3941C>T	p.Pro1314Leu	missense_variant	Exon 23 of 24	5	NM_001083603.3	ENSP00000389744.2

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

GnomAD2 exomes

AF:

0.389

AC:

95817

AN:

246178

AF XY:

0.388

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 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

African (AFR)

AF:

0.230

AC:

7694

AN:

33480

American (AMR)

AF:

0.476

AC:

21269

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.315

AC:

8227

AN:

26136

East Asian (EAS)

AF:

0.583

AC:

23162

AN:

39700

South Asian (SAS)

AF:

0.451

AC:

38914

AN:

86258

European-Finnish (FIN)

AF:

0.409

AC:

21494

AN:

52518

Middle Eastern (MID)

AF:

0.316

AC:

1820

AN:

5762

European-Non Finnish (NFE)

AF:

0.338

AC:

375366

AN:

1111956

Other (OTH)

AF:

0.358

AC:

21619

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.548

Heterozygous variant carriers

22654

45307

67961

90614

113268

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12364

24728

37092

49456

61820

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.330

AC:

50158

AN:

152072

Hom.:

8748

Cov.:

AF XY:

0.338

AC XY:

25139

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.232

AC:

9637

AN:

41524

American (AMR)

AF:

0.387

AC:

5922

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.321

AC:

1115

AN:

3472

East Asian (EAS)

AF:

0.563

AC:

2879

AN:

5112

South Asian (SAS)

AF:

0.472

AC:

2271

AN:

4814

European-Finnish (FIN)

AF:

0.399

AC:

4234

AN:

10608

Middle Eastern (MID)

AF:

0.310

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.337

AC:

22872

AN:

67946

Other (OTH)

AF:

0.337

AC:

712

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

Heterozygous variant carriers

1799

3597

5396

7194

8993

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

512

1024

1536

2048

2560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.337

Hom.:

35320

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:18Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 -

Feb 29, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:5

May 24, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:research

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29081410, 24728327, 27153395, 15888139, 22703879) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Gorlin syndrome

Benign:4

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Holoprosencephaly 7

Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Basal cell nevus syndrome 1

Benign:1

Dec 19, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Dec 01, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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;.;.;.;.;.;.

PhyloP100

9.5

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

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over