rs1805155

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000264.5(PTCH1):c.1665T>C(p.Asn555Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,613,586 control chromosomes in the GnomAD database, including 9,731 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1282 hom., cov: 32)

Exomes 𝑓: 0.11 ( 8449 hom. )

Consequence

PTCH1
NM_000264.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -1.50

Publications

38 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 9-95476097-A-G is Benign according to our data. Variant chr9-95476097-A-G is described in ClinVar as Benign. ClinVar VariationId is 138834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.5 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5 link	c.1665T>C	p.Asn555Asn	synonymous_variant	Exon 12 of 24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3 link	c.1662T>C	p.Asn554Asn	synonymous_variant	Exon 12 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.1665T>C	p.Asn555Asn	synonymous_variant	Exon 12 of 24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6 link	c.1662T>C	p.Asn554Asn	synonymous_variant	Exon 12 of 24	5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes

AF:

0.122

AC:

18581

AN:

152034

Hom.:

1272

Cov.:

show subpopulations

Gnomad AFR

AF:

0.178

Gnomad AMI

AF:

0.0581

Gnomad AMR

AF:

0.0825

Gnomad ASJ

AF:

0.0571

Gnomad EAS

AF:

0.104

Gnomad SAS

AF:

0.0593

Gnomad FIN

AF:

0.109

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.110

Gnomad OTH

AF:

0.102

GnomAD2 exomes

AF:

0.0992

AC:

24820

AN:

250302

AF XY:

0.0966

show subpopulations

Gnomad AFR exome

AF:

0.180

Gnomad AMR exome

AF:

0.0605

Gnomad ASJ exome

AF:

0.0599

Gnomad EAS exome

AF:

0.106

Gnomad FIN exome

AF:

0.111

Gnomad NFE exome

AF:

0.110

Gnomad OTH exome

AF:

0.0988

GnomAD4 exome

AF:

0.105

AC:

153734

AN:

1461434

Hom.:

8449

Cov.:

AF XY:

0.104

AC XY:

75456

AN XY:

726984

show subpopulations

African (AFR)

AF:

0.177

AC:

5930

AN:

33472

American (AMR)

AF:

0.0626

AC:

2800

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.0602

AC:

1574

AN:

26132

East Asian (EAS)

AF:

0.107

AC:

4230

AN:

39684

South Asian (SAS)

AF:

0.0592

AC:

5106

AN:

86180

European-Finnish (FIN)

AF:

0.115

AC:

6124

AN:

53354

Middle Eastern (MID)

AF:

0.0774

AC:

446

AN:

5766

European-Non Finnish (NFE)

AF:

0.109

AC:

121475

AN:

1111766

Other (OTH)

AF:

0.100

AC:

6049

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

8657

17315

25972

34630

43287

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4368

8736

13104

17472

21840

<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:

0.122

AC:

18623

AN:

152152

Hom.:

1282

Cov.:

AF XY:

0.119

AC XY:

8873

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.178

AC:

7381

AN:

41496

American (AMR)

AF:

0.0824

AC:

1260

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0571

AC:

198

AN:

3466

East Asian (EAS)

AF:

0.103

AC:

533

AN:

5160

South Asian (SAS)

AF:

0.0585

AC:

282

AN:

4820

European-Finnish (FIN)

AF:

0.109

AC:

1153

AN:

10608

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.110

AC:

7503

AN:

68002

Other (OTH)

AF:

0.110

AC:

233

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

835

1670

2504

3339

4174

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

210

420

630

840

1050

<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:

0.112

Hom.:

507

Bravo

AF:

0.123

Asia WGS

AF:

0.104

AC:

361

AN:

3478

EpiCase

AF:

0.101

EpiControl

AF:

0.100

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

Gorlin syndrome

Benign:3

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

not provided

Benign:3

Nov 04, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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.1665T>C (p.Asn555Asn) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE site of SRp55. This variant was found in 12470/115592 control chromosomes (719 homozygotes) at a frequency of 0.1078794, which is approximately 6295 times the estimated maximal allele frequency of a pathogenic PTCH1 variant (0.0000171), suggesting this variant is a benign polymorphism. This variant has been reported in multiple affected individuals in co-occurrence with different pathogenic variants (Pastorino_Human_Mutation_2005), further supporting the benign classification. In addition, another clinical diagnostic laboratory classified this variant as benign. Taken together, this variant is classified as benign. -

Hereditary cancer-predisposing syndrome

Benign:3

Jan 30, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Mar 25, 2025

Hereditary Cancer Laboratory, Hospital Universitario 12 de Octubre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BP7Supporting+BP6Supporting+BP4Supporting+BS2Strong+BA1Very strong -

Dec 04, 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. -

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

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.26

(source)

DANN

Benign

0.52

PhyloP100

-1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

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