rs2236405

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000264.5(PTCH1):c.3583A>T(p.Thr1195Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0223 in 1,557,458 control chromosomes in the GnomAD database, including 1,174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.047 ( 348 hom., cov: 33)

Exomes 𝑓: 0.020 ( 826 hom. )

Consequence

PTCH1
NM_000264.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.02

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a modified_residue Phosphothreonine (size 0) in uniprot entity PTC1_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.0019354224).

BP6

Variant 9-95449290-T-A is Benign according to our data. Variant chr9-95449290-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 135100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95449290-T-A is described in Lovd as [Benign]. Variant chr9-95449290-T-A is described in Lovd as [Pathogenic].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5 link	c.3583A>T	p.Thr1195Ser	missense_variant	Exon 22 of 24	ENST00000331920.11	NP_000255.2	Q13635-1
PTCH1	NM_001083603.3 link	c.3580A>T	p.Thr1194Ser	missense_variant	Exon 22 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.3583A>T	p.Thr1195Ser	missense_variant	Exon 22 of 24	5	NM_000264.5	ENSP00000332353.6		Q13635-1
PTCH1	ENST00000437951.6 link	c.3580A>T	p.Thr1194Ser	missense_variant	Exon 22 of 24	5	NM_001083603.3	ENSP00000389744.2		Q13635-2

Frequencies

GnomAD3 genomes

AF:

0.0469

AC:

7130

AN:

152148

Hom.:

347

Cov.:

show subpopulations

Gnomad AFR

AF:

0.116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0214

Gnomad ASJ

AF:

0.0415

Gnomad EAS

AF:

0.134

Gnomad SAS

AF:

0.0532

Gnomad FIN

AF:

0.00668

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0113

Gnomad OTH

AF:

0.0325

GnomAD3 exomes

AF:

0.0340

AC:

5516

AN:

162192

Hom.:

228

AF XY:

0.0339

AC XY:

2919

AN XY:

85986

show subpopulations

Gnomad AFR exome

AF:

0.114

Gnomad AMR exome

AF:

0.0128

Gnomad ASJ exome

AF:

0.0425

Gnomad EAS exome

AF:

0.132

Gnomad SAS exome

AF:

0.0481

Gnomad FIN exome

AF:

0.00844

Gnomad NFE exome

AF:

0.0125

Gnomad OTH exome

AF:

0.0254

GnomAD4 exome

AF:

0.0197

AC:

27632

AN:

1405192

Hom.:

826

Cov.:

AF XY:

0.0202

AC XY:

14008

AN XY:

693950

show subpopulations

Gnomad4 AFR exome

AF:

0.122

Gnomad4 AMR exome

AF:

0.0137

Gnomad4 ASJ exome

AF:

0.0441

Gnomad4 EAS exome

AF:

0.127

Gnomad4 SAS exome

AF:

0.0472

Gnomad4 FIN exome

AF:

0.00728

Gnomad4 NFE exome

AF:

0.0106

Gnomad4 OTH exome

AF:

0.0287

GnomAD4 genome

AF:

0.0469

AC:

7148

AN:

152266

Hom.:

348

Cov.:

AF XY:

0.0478

AC XY:

3558

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.116

Gnomad4 AMR

AF:

0.0213

Gnomad4 ASJ

AF:

0.0415

Gnomad4 EAS

AF:

0.134

Gnomad4 SAS

AF:

0.0539

Gnomad4 FIN

AF:

0.00668

Gnomad4 NFE

AF:

0.0113

Gnomad4 OTH

AF:

0.0321

Alfa

AF:

0.0218

Hom.:

Bravo

AF:

0.0509

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.0153

AC:

ESP6500AA

AF:

0.0976

AC:

426

ESP6500EA

AF:

0.0131

AC:

111

ExAC

AF:

0.0243

AC:

2734

Asia WGS

AF:

0.0810

AC:

281

AN:

3478

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:5Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 13, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Mar 02, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:5

Aug 27, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is found in PTCH panel(s). -

Nov 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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.3583A>T (p.Thr1195Ser) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1271/23496 control chromosomes (51 homozygotes) at a frequency of 0.0540943, which is approximately 3157 times the estimated maximal expected allele frequency of a pathogenic PTCH1 variant (0.0000171), suggesting this variant is likely a benign polymorphism. This variant has been reported in NBCCS patients. One patient also carried a potentially pathogenic variant c.3499G>A (p.G1167R), further supporting the benign classification. In addition, multiple clinical diagnostic laboratories classified this variant as benign. Taken together, this variant is classified as benign. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Gorlin syndrome

Benign:3

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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:2

Dec 03, 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. -

Dec 09, 2019

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Holoprosencephaly 7

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.52

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

Eigen

Benign

0.043

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.87

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

MetaRNN

Benign

0.0019

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

MetaSVM

Benign

-0.86

MutationAssessor

Uncertain

2.3

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

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.8

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

REVEL

Uncertain

0.43

Sift

Benign

0.086

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

Sift4G

Benign

0.24

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

Polyphen

0.47

P;.;.;B;B;.;P

Vest4

0.25

MPC

0.60

ClinPred

0.016

GERP RS

4.6

Varity_R

0.15

gMVP

0.56

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over