rs1805153

Positions:

• chr9-95506483-G-A
• chr9-95506483-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000264.5(PTCH1):​c.318C>T​(p.Leu106Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0208 in 1,613,524 control chromosomes in the GnomAD database, including 464 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (24 hom., cov: 32)
  • Exomes 𝑓: 0.021 (440 hom.)
• Consequence: PTCH1 NM_000264.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.470

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 9-95506483-G-A is Benign according to our data. Variant chr9-95506483-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 132719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95506483-G-A is described in Lovd as [Benign]. Variant chr9-95506483-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.47 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0154 (2337/152212) while in subpopulation NFE AF= 0.0242 (1644/68016). AF 95% confidence interval is 0.0232. There are 24 homozygotes in gnomad4. There are 1071 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2337 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.318C>T	p.Leu106Leu	synonymous_variant	2/24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.315C>T	p.Leu105Leu	synonymous_variant	2/24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.318C>T	p.Leu106Leu	synonymous_variant	2/24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.315C>T	p.Leu105Leu	synonymous_variant	2/24	5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2338 AN: 152096 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.00468

Gnomad AMI AF: 0.0286

Gnomad AMR AF: 0.0173

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.00764

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.0242

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.0144 AC: 3609 AN: 250738 Hom.: 32 AF XY: 0.0144 AC XY: 1954 AN XY: 135652

Gnomad AFR exome AF: 0.00413

Gnomad AMR exome AF: 0.0117

Gnomad ASJ exome AF: 0.0145

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00488

Gnomad FIN exome AF: 0.00614

Gnomad NFE exome AF: 0.0230

Gnomad OTH exome AF: 0.0165

GnomAD4 exome AF: 0.0213 AC: 31170 AN: 1461312 Hom.: 440 Cov.: 31 AF XY: 0.0209 AC XY: 15200 AN XY: 726962

Gnomad4 AFR exome AF: 0.00338

Gnomad4 AMR exome AF: 0.0118

Gnomad4 ASJ exome AF: 0.0149

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00533

Gnomad4 FIN exome AF: 0.00623

Gnomad4 NFE exome AF: 0.0253

Gnomad4 OTH exome AF: 0.0181

GnomAD4 genome AF: 0.0154 AC: 2337 AN: 152212 Hom.: 24 Cov.: 32 AF XY: 0.0144 AC XY: 1071 AN XY: 74432

Gnomad4 AFR AF: 0.00467

Gnomad4 AMR AF: 0.0173

Gnomad4 ASJ AF: 0.0164

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.00764

Gnomad4 NFE AF: 0.0242

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0197 Hom.: 11

Bravo AF: 0.0157

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0243

EpiControl AF: 0.0273

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gorlin syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	- -
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.318C>T (p.Leu106Leu) variant causes a synonymous change involving a non-conserved nucleotide with 5/5 splice prediction tools predicting no significant impact on splicing and ESE finder predicting the elimination of an ESE binding site. However, these predictions have yet to be functionally assessed. The variant was observed in the large, broad control population, ExAC, with an allele frequency of 1737/120658 (10 homozygotes, 1/69, frequency: 0.0143961), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic PTCH1 variant of 1/58479 (0.0000171), suggesting this variant is likely a benign polymorphism. The variant has been reported in affected individuals via publications and/or reputable clinical laboratories with a classification of "polymorphism/benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 16, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 09, 2016

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. -

Gorlin syndrome;C1835820:Holoprosencephaly 7;C2751544:Basal cell carcinoma, susceptibility to, 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 29, 2022

- -

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	-0.47
CADD	Benign	15
DANN	Benign	0.93

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: rs1805153; hg19: chr9-98268765;