9-95508364-TGCCGCCGCCGCC-TGCCGCCGCC

Position:

• chr9-95508364-TGCCGCCGCCGCC-TGCCGCCGCC

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.-6_-4delGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000833 in 1,154,618 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 22)
  • Exomes 𝑓: 0.00079 (2 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-TGCC-T is Benign according to our data. Variant chr9-95508364-TGCC-T is described in ClinVar as [Likely_benign]. Clinvar id is 215455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95508364-TGCC-T is described in Lovd as [Likely_benign]. Variant chr9-95508364-TGCC-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00111 (164/147830) while in subpopulation EAS AF= 0.00546 (27/4948). AF 95% confidence interval is 0.00385. There are 0 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 164 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.-6_-4delGGC		5_prime_UTR_variant	1/24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.199-1768_199-1766delGGC		intron_variant		ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.-6_-4delGGC		5_prime_UTR_variant	1/24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.199-1768_199-1766delGGC		intron_variant		5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 163 AN: 147724 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00100

Gnomad ASJ AF: 0.000294

Gnomad EAS AF: 0.00544

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000213

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000316

Gnomad OTH AF: 0.00148

GnomAD3 exomes AF: 0.00134 AC: 2 AN: 1492 Hom.: 0 AF XY: 0.00116 AC XY: 1 AN XY: 862

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00158

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000793 AC: 798 AN: 1006788 Hom.: 2 AF XY: 0.000810 AC XY: 386 AN XY: 476420

Gnomad4 AFR exome AF: 0.00225

Gnomad4 AMR exome AF: 0.00260

Gnomad4 ASJ exome AF: 0.00136

Gnomad4 EAS exome AF: 0.00402

Gnomad4 SAS exome AF: 0.000583

Gnomad4 FIN exome AF: 0.00244

Gnomad4 NFE exome AF: 0.000609

Gnomad4 OTH exome AF: 0.00135

GnomAD4 genome AF: 0.00111 AC: 164 AN: 147830 Hom.: 0 Cov.: 22 AF XY: 0.00114 AC XY: 82 AN XY: 72032

Gnomad4 AFR AF: 0.00231

Gnomad4 AMR AF: 0.00100

Gnomad4 ASJ AF: 0.000294

Gnomad4 EAS AF: 0.00546

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000213

Gnomad4 NFE AF: 0.000316

Gnomad4 OTH AF: 0.00196

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 27, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 18, 2021	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PTCH1: BP4, BS1 -

Gorlin syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 24, 2016

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2020

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. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs71366293; hg19: chr9-98270646;