rs2227970

Positions:

• chr9-95468802-T-C
• chr9-95468802-T-G

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.2199A>G​(p.Ser733=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 1,614,154 control chromosomes in the GnomAD database, including 224 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (28 hom., cov: 32)
  • Exomes 𝑓: 0.016 (196 hom.)
• Consequence: PTCH1 NM_000264.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -1.34

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]

LOC100507346 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 9-95468802-T-C is Benign according to our data. Variant chr9-95468802-T-C is described in ClinVar as [Benign]. Clinvar id is 132699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95468802-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.34 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0118 (1797/152274) while in subpopulation EAS AF= 0.0307 (159/5182). AF 95% confidence interval is 0.0268. There are 28 homozygotes in gnomad4. There are 922 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1797 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH1	NM_000264.5	c.2199A>G	p.Ser733=	synonymous_variant	14/24	ENST00000331920.11
PTCH1	NM_001083603.3	c.2196A>G	p.Ser732=	synonymous_variant	14/24	ENST00000437951.6
LOC100507346	NR_038982.1	n.740T>C		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11	c.2199A>G	p.Ser733=	synonymous_variant	14/24	5	NM_000264.5	A2
PTCH1	ENST00000437951.6	c.2196A>G	p.Ser732=	synonymous_variant	14/24	5	NM_001083603.3

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1777 AN: 152156 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.00292

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00969

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.0308

Gnomad SAS AF: 0.0238

Gnomad FIN AF: 0.0120

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0145 AC: 3639 AN: 251494 Hom.: 37 AF XY: 0.0154 AC XY: 2099 AN XY: 135922

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00685

Gnomad ASJ exome AF: 0.0141

Gnomad EAS exome AF: 0.0290

Gnomad SAS exome AF: 0.0214

Gnomad FIN exome AF: 0.0119

Gnomad NFE exome AF: 0.0147

Gnomad OTH exome AF: 0.0171

GnomAD4 exome AF: 0.0157 AC: 22997 AN: 1461880 Hom.: 196 Cov.: 33 AF XY: 0.0158 AC XY: 11525 AN XY: 727242

Gnomad4 AFR exome AF: 0.00185

Gnomad4 AMR exome AF: 0.00698

Gnomad4 ASJ exome AF: 0.0135

Gnomad4 EAS exome AF: 0.0252

Gnomad4 SAS exome AF: 0.0190

Gnomad4 FIN exome AF: 0.0119

Gnomad4 NFE exome AF: 0.0161

Gnomad4 OTH exome AF: 0.0164

GnomAD4 genome AF: 0.0118 AC: 1797 AN: 152274 Hom.: 28 Cov.: 32 AF XY: 0.0124 AC XY: 922 AN XY: 74462

Gnomad4 AFR AF: 0.00291

Gnomad4 AMR AF: 0.00967

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.0307

Gnomad4 SAS AF: 0.0238

Gnomad4 FIN AF: 0.0120

Gnomad4 NFE AF: 0.0152

Gnomad4 OTH AF: 0.0208

Alfa AF: 0.0133 Hom.: 6

Bravo AF: 0.0106

Asia WGS AF: 0.0550 AC: 190 AN: 3478

EpiCase AF: 0.0156

EpiControl AF: 0.0156

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

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.2199A>G (p.Ser733Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant, 5/5 Alamut algorithms predict no change to splicing, and ESEfinder predicts the creation of exonic splice enhancers. However, these in silico predictions have not been validated by in vivo/vitro studies. This variant was found in 1767/121406 control chromosomes (21 homozygotes) at a frequency of 0.0145545, which is approximately 849 times the estimated maximal expected allele frequency of a pathogenic PTCH1 variant (0.0000171), highly suggesting this variant is a benign polymorphism. In addition, one clinical diagnostic laboratory classified this variant as benign. Based on the high prevalence in the general population, this variant was classified as Benign. -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 19, 2021	- -

Gorlin syndrome Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 17, 2015	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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 24, 2020	- -

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	-0.62
CADD	Benign	0.33
DANN	Benign	0.66

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: rs2227970; hg19: chr9-98231084;