NM_000264.5:c.1504-8T>C

Variant names:

• chr9-95476865-A-G
• rs2277184
• NM_000264.5:c.1504-8T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000264.5(PTCH1):​c.1504-8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0269 in 1,612,438 control chromosomes in the GnomAD database, including 2,220 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.071 (899 hom., cov: 32)
  • Exomes 𝑓: 0.022 (1321 hom.)
• Consequence: PTCH1 NM_000264.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001998
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.613
• Publications: 14 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 9-95476865-A-G is Benign according to our data. Variant chr9-95476865-A-G is described in ClinVar as Benign. ClinVar VariationId is 255669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000264.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH1	NM_000264.5	MANE Select	c.1504-8T>C		splice_region intron	N/A	NP_000255.2
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.1501-8T>C		splice_region intron	N/A	NP_001077072.1
	PTCH1	NM_001354918.2		c.1348-8T>C		splice_region intron	N/A	NP_001341847.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH1	ENST00000331920.11	TSL:5 MANE Select	c.1504-8T>C		splice_region intron	N/A	ENSP00000332353.6
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.1501-8T>C		splice_region intron	N/A	ENSP00000389744.2
	PTCH1	ENST00000429896.6	TSL:1	c.1051-8T>C		splice_region intron	N/A	ENSP00000414823.2

Frequencies

GnomAD3 genomes AF: 0.0710 AC: 10797 AN: 152172 Hom.: 894 Cov.: 32

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.0321

Gnomad ASJ AF: 0.0412

Gnomad EAS AF: 0.137

Gnomad SAS AF: 0.0513

Gnomad FIN AF: 0.00677

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0115

Gnomad OTH AF: 0.0516

GnomAD2 exomes AF: 0.0407 AC: 10169 AN: 249778 AF XY: 0.0378

Gnomad AFR exome AF: 0.205

Gnomad AMR exome AF: 0.0191

Gnomad ASJ exome AF: 0.0414

Gnomad EAS exome AF: 0.140

Gnomad FIN exome AF: 0.00824

Gnomad NFE exome AF: 0.0125

Gnomad OTH exome AF: 0.0284

GnomAD4 exome AF: 0.0222 AC: 32471 AN: 1460148 Hom.: 1321 Cov.: 31 AF XY: 0.0223 AC XY: 16231 AN XY: 726422

African (AFR) AF: 0.201 AC: 6707 AN: 33394

American (AMR) AF: 0.0203 AC: 907 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.0435 AC: 1136 AN: 26128

East Asian (EAS) AF: 0.130 AC: 5165 AN: 39640

South Asian (SAS) AF: 0.0472 AC: 4064 AN: 86076

European-Finnish (FIN) AF: 0.00761 AC: 406 AN: 53382

Middle Eastern (MID) AF: 0.0291 AC: 168 AN: 5766

European-Non Finnish (NFE) AF: 0.0107 AC: 11837 AN: 1110742

Other (OTH) AF: 0.0345 AC: 2081 AN: 60334

GnomAD4 genome AF: 0.0711 AC: 10835 AN: 152290 Hom.: 899 Cov.: 32 AF XY: 0.0711 AC XY: 5296 AN XY: 74476

African (AFR) AF: 0.196 AC: 8128 AN: 41516

American (AMR) AF: 0.0321 AC: 491 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0412 AC: 143 AN: 3468

East Asian (EAS) AF: 0.137 AC: 709 AN: 5186

South Asian (SAS) AF: 0.0518 AC: 250 AN: 4826

European-Finnish (FIN) AF: 0.00677 AC: 72 AN: 10632

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0115 AC: 785 AN: 68040

Other (OTH) AF: 0.0515 AC: 109 AN: 2116

Alfa AF: 0.0420 Hom.: 884

Bravo AF: 0.0785

Asia WGS AF: 0.0960 AC: 333 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gorlin syndrome Benign:4

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

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.

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 26, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: 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.1504-8T>C variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 5281/110876 control chromosomes (329 homozygotes) at a frequency of 0.0476298, which is approximately 2779 times the estimated maximal expected allele frequency of a pathogenic PTCH1 variant (0.0000171), suggesting this variant is likely a benign polymorphism. Taken together, this variant is classified as benign.

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:2

PreventionGenetics, part of Exact Sciences

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

Hereditary cancer-predisposing syndrome Benign:1

Feb 19, 2019

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 Benign:1

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.83
DANN	Benign	0.55
PhyloP100		-0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs2277184; hg19: chr9-98239147; COSMIC: COSV59476967; COSMIC: COSV59476967;