rs73527759

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001083603.3(PTCH1):c.163G>C(p.Asp55His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00495 in 1,611,754 control chromosomes in the GnomAD database, including 274 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 136 hom., cov: 31)

Exomes 𝑓: 0.0029 ( 138 hom. )

Consequence

PTCH1
NM_001083603.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: 1.92

Publications

7 publications found

Variant links:

COSMIC-nc: COSV64603597

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=0.0015723407).

BP6

Variant 9-95516658-C-G is Benign according to our data. Variant chr9-95516658-C-G is described in ClinVar as Benign. ClinVar VariationId is 41769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0801 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PTCH1	NM_001083603.3 link	c.163G>C	p.Asp55His	missense_variant	Exon 1 of 24	ENST00000437951.6	NP_001077072.1
PTCH1	NM_001083602.3 link	c.-187G>C		5_prime_UTR_variant	Exon 1 of 24		NP_001077071.1
PTCH1	NM_001354919.2 link	c.-187G>C		5_prime_UTR_variant	Exon 1 of 5		NP_001341848.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000437951.6 link	c.163G>C	p.Asp55His	missense_variant	Exon 1 of 24	5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes

AF:

0.0243

AC:

3687

AN:

151960

Hom.:

133

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0823

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0125

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000471

Gnomad OTH

AF:

0.0191

GnomAD2 exomes

AF:

0.00664

AC:

1632

AN:

245646

AF XY:

0.00515

show subpopulations

Gnomad AFR exome

AF:

0.0856

Gnomad AMR exome

AF:

0.00586

Gnomad ASJ exome

AF:

0.00550

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000931

Gnomad NFE exome

AF:

0.000413

Gnomad OTH exome

AF:

0.00420

GnomAD4 exome

AF:

0.00294

AC:

4287

AN:

1459676

Hom.:

138

Cov.:

AF XY:

0.00263

AC XY:

1908

AN XY:

726138

show subpopulations

African (AFR)

AF:

0.0893

AC:

2978

AN:

33334

American (AMR)

AF:

0.00666

AC:

296

AN:

44418

Ashkenazi Jewish (ASJ)

AF:

0.00563

AC:

147

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39614

South Asian (SAS)

AF:

0.0000815

AC:

AN:

85936

European-Finnish (FIN)

AF:

0.0000568

AC:

AN:

52854

Middle Eastern (MID)

AF:

0.00417

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.000365

AC:

406

AN:

1111378

Other (OTH)

AF:

0.00707

AC:

426

AN:

60264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

222

444

667

889

1111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

204

306

408

510

<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:

0.0243

AC:

3699

AN:

152078

Hom.:

136

Cov.:

AF XY:

0.0237

AC XY:

1762

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.0824

AC:

3416

AN:

41470

American (AMR)

AF:

0.0124

AC:

190

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5134

South Asian (SAS)

AF:

0.000622

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0000945

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000471

AC:

AN:

67974

Other (OTH)

AF:

0.0189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

168

336

504

672

840

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:

0.00802

Hom.:

Bravo

AF:

0.0282

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0787

AC:

297

ESP6500EA

AF:

0.000610

AC:

ExAC

AF:

0.00740

AC:

894

Asia WGS

AF:

0.00693

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000594

ClinVar

Significance: Benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:research

- -

Oct 14, 2023

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

- -

not specified

Benign:2Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Classification criteria: BA1 -

Oct 24, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.65

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.29

MetaRNN

Benign

0.0016

MetaSVM

Benign

-0.80

PhyloP100

1.9

PROVEAN

Benign

-0.19

REVEL

Benign

0.14

Sift

Benign

0.072

Sift4G

Benign

0.18

Polyphen

0.042

Vest4

0.30

MVP

0.29

ClinPred

0.0057

GERP RS

3.1

PromoterAI

0.034

Neutral

(source)

Mutation Taster

=90/10

polymorphism (auto)

(source)

Splicing

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