rs1805155

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000264.5(PTCH1):c.1665T>C(p.Asn555=) 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:11

Conservation

PhyloP100: -1.50

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 -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 id is 138834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95476097-A-G is described in Lovd as [Benign].

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/exons	MANE	UniProt
PTCH1	NM_000264.5 linkuse as main transcript	c.1665T>C	p.Asn555=	synonymous_variant	12/24	ENST00000331920.11
PTCH1	NM_001083603.3 linkuse as main transcript	c.1662T>C	p.Asn554=	synonymous_variant	12/24	ENST00000437951.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11 linkuse as main transcript	c.1665T>C	p.Asn555=	synonymous_variant	12/24	5	NM_000264.5	A2	Q13635-1
PTCH1	ENST00000437951.6 linkuse as main transcript	c.1662T>C	p.Asn554=	synonymous_variant	12/24	5	NM_001083603.3		Q13635-2

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

GnomAD3 exomes

AF:

0.0992

AC:

24820

AN:

250302

Hom.:

1383

AF XY:

0.0966

AC XY:

13075

AN XY:

135318

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 SAS exome

AF:

0.0592

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

Gnomad4 AFR exome

AF:

0.177

Gnomad4 AMR exome

AF:

0.0626

Gnomad4 ASJ exome

AF:

0.0602

Gnomad4 EAS exome

AF:

0.107

Gnomad4 SAS exome

AF:

0.0592

Gnomad4 FIN exome

AF:

0.115

Gnomad4 NFE exome

AF:

0.109

Gnomad4 OTH exome

AF:

0.100

GnomAD4 genome

AF:

0.122

AC:

18623

AN:

152152

Hom.:

1282

Cov.:

AF XY:

0.119

AC XY:

8873

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.178

Gnomad4 AMR

AF:

0.0824

Gnomad4 ASJ

AF:

0.0571

Gnomad4 EAS

AF:

0.103

Gnomad4 SAS

AF:

0.0585

Gnomad4 FIN

AF:

0.109

Gnomad4 NFE

AF:

0.110

Gnomad4 OTH

AF:

0.110

Alfa

AF:

0.111

Hom.:

502

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:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Gorlin syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 24, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 04, 2014	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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 30, 2020	- -

Holoprosencephaly 7

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.26

DANN

Benign

0.52

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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