NM_000264.5:c.735A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000264.5(PTCH1):c.735A>G(p.Thr245Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0303 in 1,610,610 control chromosomes in the GnomAD database, including 953 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 60 hom., cov: 32)

Exomes 𝑓: 0.031 ( 893 hom. )

Consequence

PTCH1
NM_000264.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -0.202

Publications

12 publications found

Variant links:

COSMIC-nc: COSV59479599

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=-0.63).

BP6

Variant 9-95481960-T-C is Benign according to our data. Variant chr9-95481960-T-C is described in ClinVar as Benign. ClinVar VariationId is 132726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.202 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0219 (3331/152328) while in subpopulation NFE AF = 0.0353 (2404/68018). AF 95% confidence interval is 0.0342. There are 60 homozygotes in GnomAd4. There are 1577 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 3331 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5 link	c.735A>G	p.Thr245Thr	synonymous_variant	Exon 5 of 24	ENST00000331920.11	NP_000255.2	Q13635-1
PTCH1	NM_001083603.3 link	c.732A>G	p.Thr244Thr	synonymous_variant	Exon 5 of 24	ENST00000437951.6	NP_001077072.1	Q13635-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11 link	c.735A>G	p.Thr245Thr	synonymous_variant	Exon 5 of 24	5	NM_000264.5	ENSP00000332353.6		Q13635-1
PTCH1	ENST00000437951.6 link	c.732A>G	p.Thr244Thr	synonymous_variant	Exon 5 of 24	5	NM_001083603.3	ENSP00000389744.2		Q13635-2

Frequencies

GnomAD3 genomes

AF:

0.0219

AC:

3331

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00547

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0178

Gnomad ASJ

AF:

0.0372

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00455

Gnomad FIN

AF:

0.0195

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0353

Gnomad OTH

AF:

0.0234

GnomAD2 exomes

AF:

0.0224

AC:

5632

AN:

251356

AF XY:

0.0227

show subpopulations

Gnomad AFR exome

AF:

0.00486

Gnomad AMR exome

AF:

0.0162

Gnomad ASJ exome

AF:

0.0387

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0182

Gnomad NFE exome

AF:

0.0340

Gnomad OTH exome

AF:

0.0287

GnomAD4 exome

AF:

0.0311

AC:

45397

AN:

1458282

Hom.:

893

Cov.:

AF XY:

0.0305

AC XY:

22138

AN XY:

725732

show subpopulations

African (AFR)

AF:

0.00470

AC:

157

AN:

33402

American (AMR)

AF:

0.0165

AC:

736

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0376

AC:

982

AN:

26118

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39676

South Asian (SAS)

AF:

0.00579

AC:

499

AN:

86180

European-Finnish (FIN)

AF:

0.0180

AC:

961

AN:

53410

Middle Eastern (MID)

AF:

0.0347

AC:

200

AN:

5764

European-Non Finnish (NFE)

AF:

0.0362

AC:

40189

AN:

1108742

Other (OTH)

AF:

0.0277

AC:

1671

AN:

60274

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

2049

4098

6147

8196

10245

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1474

2948

4422

5896

7370

<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:

0.0219

AC:

3331

AN:

152328

Hom.:

Cov.:

AF XY:

0.0212

AC XY:

1577

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00546

AC:

227

AN:

41588

American (AMR)

AF:

0.0178

AC:

272

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0372

AC:

129

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00435

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0195

AC:

207

AN:

10618

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0353

AC:

2404

AN:

68018

Other (OTH)

AF:

0.0232

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

168

336

503

671

839

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0295

Hom.:

Bravo

AF:

0.0219

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0357

EpiControl

AF:

0.0384

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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

Significance:Benign

Review Status:no assertion criteria provided

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 31, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

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.735A>G (p.Thr245Thr) 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 along with 5/5 splice site prediction tools predicting the variant not to have an impact on splicing. This variant was found in 2760/120306 control chromosomes (42 homozygotes) at a frequency of 0.0229415, which is approximately 1339 times the estimated maximal expected allele frequency of a pathogenic PTCH1 variant (0.0000171), suggesting this variant is likely a benign polymorphism. One clinical diagnostic laboratory classified this variant as Benign. Additionally, the variant has been reported in the literature as a polymorphism (Musani_Gene_2013).Taken together and based on the high frequency in the general population, this variant is classified as Benign. -

Mar 03, 2015

GeneDx

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

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Gorlin syndrome

Benign:3

Jan 12, 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

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

May 04, 2016

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;C2751544:Basal cell carcinoma, susceptibility to, 1;CN376810:Basal cell nevus syndrome 1

Benign:1

Jul 26, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Holoprosencephaly 7

Benign:1

Jan 12, 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

-0.63

CADD

Benign

5.7

(source)

DANN

Benign

0.48

PhyloP100

-0.20

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