rs1805153

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_StrongBP7BS1BS2

The NM_000264.5(PTCH1):c.318C>T(p.Leu106Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0208 in 1,613,524 control chromosomes in the GnomAD database, including 464 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 24 hom., cov: 32)

Exomes 𝑓: 0.021 ( 440 hom. )

Consequence

PTCH1
NM_000264.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.470

Publications

11 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:

ENSG00000271155 (HGNC:):

ENSG00000271155 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=-0.47).

BP6

Variant 9-95506483-G-A is Benign according to our data. Variant chr9-95506483-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 132719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.47 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0154 (2337/152212) while in subpopulation NFE AF = 0.0242 (1644/68016). AF 95% confidence interval is 0.0232. There are 24 homozygotes in GnomAd4. There are 1071 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2337 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5 link	c.318C>T	p.Leu106Leu	synonymous_variant	Exon 2 of 24	ENST00000331920.11	NP_000255.2	Q13635-1
PTCH1	NM_001083603.3 link	c.315C>T	p.Leu105Leu	synonymous_variant	Exon 2 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.318C>T	p.Leu106Leu	synonymous_variant	Exon 2 of 24	5	NM_000264.5	ENSP00000332353.6		Q13635-1
PTCH1	ENST00000437951.6 link	c.315C>T	p.Leu105Leu	synonymous_variant	Exon 2 of 24	5	NM_001083603.3	ENSP00000389744.2		Q13635-2

Frequencies

GnomAD3 genomes

AF:

0.0154

AC:

2338

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00468

Gnomad AMI

AF:

0.0286

Gnomad AMR

AF:

0.0173

Gnomad ASJ

AF:

0.0164

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00477

Gnomad FIN

AF:

0.00764

Gnomad MID

AF:

0.0446

Gnomad NFE

AF:

0.0242

Gnomad OTH

AF:

0.0163

GnomAD2 exomes

AF:

0.0144

AC:

3609

AN:

250738

AF XY:

0.0144

show subpopulations

Gnomad AFR exome

AF:

0.00413

Gnomad AMR exome

AF:

0.0117

Gnomad ASJ exome

AF:

0.0145

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00614

Gnomad NFE exome

AF:

0.0230

Gnomad OTH exome

AF:

0.0165

GnomAD4 exome

AF:

0.0213

AC:

31170

AN:

1461312

Hom.:

440

Cov.:

AF XY:

0.0209

AC XY:

15200

AN XY:

726962

show subpopulations

African (AFR)

AF:

0.00338

AC:

113

AN:

33454

American (AMR)

AF:

0.0118

AC:

526

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.0149

AC:

390

AN:

26114

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39658

South Asian (SAS)

AF:

0.00533

AC:

459

AN:

86166

European-Finnish (FIN)

AF:

0.00623

AC:

333

AN:

53414

Middle Eastern (MID)

AF:

0.0176

AC:

101

AN:

5728

European-Non Finnish (NFE)

AF:

0.0253

AC:

28152

AN:

1111740

Other (OTH)

AF:

0.0181

AC:

1094

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

1733

3467

5200

6934

8667

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1062

2124

3186

4248

5310

<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:

0.0154

AC:

2337

AN:

152212

Hom.:

Cov.:

AF XY:

0.0144

AC XY:

1071

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00467

AC:

194

AN:

41534

American (AMR)

AF:

0.0173

AC:

264

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0164

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00477

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00764

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.0479

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0242

AC:

1644

AN:

68016

Other (OTH)

AF:

0.0161

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

118

236

353

471

589

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0208

Hom.:

Bravo

AF:

0.0157

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0243

EpiControl

AF:

0.0273

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 16, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: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

- -

Gorlin syndrome

Benign:3

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. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

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.318C>T (p.Leu106Leu) variant causes a synonymous change involving a non-conserved nucleotide with 5/5 splice prediction tools predicting no significant impact on splicing and ESE finder predicting the elimination of an ESE binding site. However, these predictions have yet to be functionally assessed. The variant was observed in the large, broad control population, ExAC, with an allele frequency of 1737/120658 (10 homozygotes, 1/69, frequency: 0.0143961), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic PTCH1 variant of 1/58479 (0.0000171), suggesting this variant is likely a benign polymorphism. The variant has been reported in affected individuals via publications and/or reputable clinical laboratories with a classification of "polymorphism/benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 07, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Sep 09, 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. -

Gorlin syndrome;C1835820:Holoprosencephaly 7;C2751544:Basal cell carcinoma, susceptibility to, 1

Benign:1

Mar 29, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Holoprosencephaly 7;C2751544:Basal cell carcinoma, susceptibility to, 1;CN376810:Basal cell nevus syndrome 1

Benign:1

Nov 30, 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 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

-0.47

CADD

Benign

(source)

DANN

Benign

0.93

PhyloP100

0.47

PromoterAI

-0.0060

Neutral

(source)

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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