rs71366293

Positions:

• 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. Variant got -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. 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:6
• Conservation: PhyloP100: 3.30

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 113 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.-15_-4delGGCGGCGGCGGC		5_prime_UTR_variant	1/24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.199-1777_199-1766delGGCGGCGGCGGC		intron_variant		ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.-15_-4delGGCGGCGGCGGC		5_prime_UTR_variant	1/24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.199-1777_199-1766delGGCGGCGGCGGC		intron_variant		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

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

Gnomad4 AFR exome AF: 0.0000496

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000580

Gnomad4 OTH exome AF: 0.000901

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0227

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000452

Gnomad4 OTH AF: 0.000978

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 17, 2024	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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 29, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 2017	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. -

PTCH1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 16, 2023

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 25, 2015

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 15, 2020

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs71366293; hg19: chr9-98270646;