9-95447411-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000264.5(PTCH1):c.3845C>T(p.Pro1282Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00165 in 1,605,002 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. P1282R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0088 ( 25 hom., cov: 33)

Exomes 𝑓: 0.00091 ( 26 hom. )

Consequence

PTCH1
NM_000264.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16O:1

Conservation

PhyloP100: 5.19

Publications

12 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=0.0031888783).

BP6

Variant 9-95447411-G-A is Benign according to our data. Variant chr9-95447411-G-A is described in ClinVar as Benign. ClinVar VariationId is 41661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00877 (1336/152294) while in subpopulation AFR AF = 0.0302 (1256/41558). AF 95% confidence interval is 0.0288. There are 25 homozygotes in GnomAd4. There are 650 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1336 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5 link	c.3845C>T	p.Pro1282Leu	missense_variant	Exon 23 of 24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3 link	c.3842C>T	p.Pro1281Leu	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.3845C>T	p.Pro1282Leu	missense_variant	Exon 23 of 24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6 link	c.3842C>T	p.Pro1281Leu	missense_variant	Exon 23 of 24	5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes

AF:

0.00880

AC:

1339

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0304

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00301

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00717

GnomAD2 exomes

AF:

0.00224

AC:

541

AN:

241766

AF XY:

0.00178

show subpopulations

Gnomad AFR exome

AF:

0.0306

Gnomad AMR exome

AF:

0.00160

Gnomad ASJ exome

AF:

0.00105

Gnomad EAS exome

AF:

0.000112

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000546

Gnomad OTH exome

AF:

0.00119

GnomAD4 exome

AF:

0.000905

AC:

1315

AN:

1452708

Hom.:

Cov.:

AF XY:

0.000803

AC XY:

580

AN XY:

722064

show subpopulations

African (AFR)

AF:

0.0291

AC:

962

AN:

33096

American (AMR)

AF:

0.00185

AC:

AN:

43770

Ashkenazi Jewish (ASJ)

AF:

0.00132

AC:

AN:

25710

East Asian (EAS)

AF:

0.000152

AC:

AN:

39594

South Asian (SAS)

AF:

0.000128

AC:

AN:

85722

European-Finnish (FIN)

AF:

0.0000196

AC:

AN:

51138

Middle Eastern (MID)

AF:

0.000527

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.0000903

AC:

100

AN:

1108016

Other (OTH)

AF:

0.00195

AC:

117

AN:

59970

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

150

226

301

376

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00877

AC:

1336

AN:

152294

Hom.:

Cov.:

AF XY:

0.00873

AC XY:

650

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0302

AC:

1256

AN:

41558

American (AMR)

AF:

0.00301

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68016

Other (OTH)

AF:

0.00710

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

140

211

281

351

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00322

Hom.:

Bravo

AF:

0.00963

ESP6500AA

AF:

0.0239

AC:

103

ESP6500EA

AF:

0.000235

AC:

ExAC

AF:

0.00265

AC:

321

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jul 11, 2025

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 26, 2021

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 14, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:5

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

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: 24728327)

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:research

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Gorlin syndrome

Benign:3

Jan 13, 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.

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary cancer-predisposing syndrome

Benign:1

Jan 28, 2015

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.

Holoprosencephaly 7

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.27

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

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.43

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.91

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

MetaRNN

Benign

0.0032

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

MetaSVM

Benign

-0.50

MutationAssessor

Uncertain

2.1

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

PhyloP100

5.2

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.50

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

REVEL

Benign

0.23

Sift

Benign

0.068

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

Sift4G

Benign

0.27

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

Vest4

0.49

ClinPred

0.012

GERP RS

2.9

Varity_R

0.074

gMVP

0.29

Mutation Taster

=99/1

polymorphism

(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