rs71366293

Variant names:

• chr9-95508364-TGCCGCCGCCGCC-T
• rs71366293
• NM_000264.5:c.-15_-4delGGCGGCGGCGGC

Your query was ambiguous. Multiple possible variants found:

• chr9-95508364-TGCCGCCGCCGCC-T
• chr9-95508364-TGCCGCCGCCGCC-TGCC
• chr9-95508364-TGCCGCCGCCGCC-TGCCGCC
• chr9-95508364-TGCCGCCGCCGCC-TGCCGCCGCC
• chr9-95508364-TGCCGCCGCCGCC-TGCCGCCGCCGCCGCC
• chr9-95508364-TGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCC
• chr9-95508364-TGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCCGCC
• chr9-95508364-TGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCCGCCGCC
• chr9-95508364-TGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCCGCCGCCGCC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000264.5(PTCH1):​c.-15_-4delGGCGGCGGCGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000516 in 1,163,786 control chromosomes in the GnomAD database, including 6 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00076 (2 hom., cov: 22)
  • Exomes 𝑓: 0.00048 (4 hom.)
• Consequence: PTCH1 NM_000264.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.30
• Publications: 2 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 -16 ACMG points.

• BP6: Variant 9-95508364-TGCCGCCGCCGCC-T is Benign according to our data. Variant chr9-95508364-TGCCGCCGCCGCC-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 219940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000764 (113/147840) while in subpopulation SAS AF = 0.0227 (108/4750). AF 95% confidence interval is 0.0193. There are 2 homozygotes in GnomAd4. There are 82 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 113 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.-15_-4delGGCGGCGGCGGC		5_prime_UTR_variant	Exon 1 of 24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.199-1777_199-1766delGGCGGCGGCGGC		intron_variant	Intron 1 of 23	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.-15_-4delGGCGGCGGCGGC		5_prime_UTR_variant	Exon 1 of 24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.199-1777_199-1766delGGCGGCGGCGGC		intron_variant	Intron 1 of 23	5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes AF: 0.000772 AC: 114 AN: 147734 Hom.: 2 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0229

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000452

Gnomad OTH AF: 0.000988

GnomAD2 exomes AF: 0.00 AC: 0 AN: 1492 AF XY: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000480 AC: 488 AN: 1015946 Hom.: 4 AF XY: 0.000539 AC XY: 259 AN XY: 480692

African (AFR) AF: 0.0000496 AC: 1 AN: 20162

American (AMR) AF: 0.00 AC: 0 AN: 6622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11094

East Asian (EAS) AF: 0.00 AC: 0 AN: 20892

South Asian (SAS) AF: 0.0209 AC: 397 AN: 19024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18176

Middle Eastern (MID) AF: 0.00156 AC: 4 AN: 2568

European-Non Finnish (NFE) AF: 0.0000580 AC: 51 AN: 878572

Other (OTH) AF: 0.000901 AC: 35 AN: 38836

GnomAD4 genome AF: 0.000764 AC: 113 AN: 147840 Hom.: 2 Cov.: 22 AF XY: 0.00114 AC XY: 82 AN XY: 72036

African (AFR) AF: 0.00 AC: 0 AN: 40744

American (AMR) AF: 0.00 AC: 0 AN: 14952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3398

East Asian (EAS) AF: 0.00 AC: 0 AN: 4948

South Asian (SAS) AF: 0.0227 AC: 108 AN: 4750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000452 AC: 3 AN: 66430

Other (OTH) AF: 0.000978 AC: 2 AN: 2046

Alfa AF: 0.00 Hom.: 138

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Sep 17, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PTCH1 c.-15_-4del12 is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.00052 in 1163786 control chromosomes in the gnomAD database, including 6 homozygotes. The observed variant frequency is approximately 30.13 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTCH1 causing Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome) phenotype (1.7e-05). To our knowledge, no occurrence of c.-15_-4del12 in individuals affected with Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome) and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 219940). Based on the evidence outlined above, the variant was classified as benign. -

Jul 12, 2017

GeneDx

Significance: Likely 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. -

Dec 29, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely 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

- -

PTCH1-related disorder Benign:1

May 16, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Gorlin syndrome Benign:1

Aug 25, 2015

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Jul 15, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=294/6	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs71366293; hg19: chr9-98270646;