rs2066836

chr9-95476076-G-Achr9-95476076-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000264.5(PTCH1):c.1686C>T(p.Ala562=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,613,506 control chromosomes in the GnomAD database, including 33,080 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A562A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.15 (2388 hom., cov: 32)
  • Exomes 𝑓: 0.20 (30692 hom.)
• Consequence: PTCH1 NM_000264.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -5.48

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 9-95476076-G-A is Benign according to our data. Variant chr9-95476076-G-A is described in ClinVar as [Benign]. Clinvar id is 255670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95476076-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-5.48 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH1	NM_000264.5	c.1686C>T	p.Ala562=	synonymous_variant	12/24	ENST00000331920.11
PTCH1	NM_001083603.3	c.1683C>T	p.Ala561=	synonymous_variant	12/24	ENST00000437951.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11	c.1686C>T	p.Ala562=	synonymous_variant	12/24	5	NM_000264.5	A2
PTCH1	ENST00000437951.6	c.1683C>T	p.Ala561=	synonymous_variant	12/24	5	NM_001083603.3

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23346 AN: 152046 Hom.: 2385 Cov.: 32

Gnomad AFR AF: 0.0358

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.270

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.221

Gnomad OTH AF: 0.166

GnomAD3 exomes AF: 0.172 AC: 43045 AN: 250444 Hom.: 4273 AF XY: 0.178 AC XY: 24033 AN XY: 135360

Gnomad AFR exome AF: 0.0309

Gnomad AMR exome AF: 0.0870

Gnomad ASJ exome AF: 0.261

Gnomad EAS exome AF: 0.104

Gnomad SAS exome AF: 0.139

Gnomad FIN exome AF: 0.230

Gnomad NFE exome AF: 0.218

Gnomad OTH exome AF: 0.192

GnomAD4 exome AF: 0.199 AC: 290845 AN: 1461342 Hom.: 30692 Cov.: 35 AF XY: 0.199 AC XY: 144598 AN XY: 726946

Gnomad4 AFR exome AF: 0.0307

Gnomad4 AMR exome AF: 0.0892

Gnomad4 ASJ exome AF: 0.268

Gnomad4 EAS exome AF: 0.0841

Gnomad4 SAS exome AF: 0.145

Gnomad4 FIN exome AF: 0.227

Gnomad4 NFE exome AF: 0.214

Gnomad4 OTH exome AF: 0.187

GnomAD4 genome AF: 0.153 AC: 23345 AN: 152164 Hom.: 2388 Cov.: 32 AF XY: 0.153 AC XY: 11371 AN XY: 74394

Gnomad4 AFR AF: 0.0357

Gnomad4 AMR AF: 0.108

Gnomad4 ASJ AF: 0.270

Gnomad4 EAS AF: 0.101

Gnomad4 SAS AF: 0.130

Gnomad4 FIN AF: 0.241

Gnomad4 NFE AF: 0.221

Gnomad4 OTH AF: 0.164

Alfa AF: 0.198 Hom.: 4323

Bravo AF: 0.139

Asia WGS AF: 0.0980 AC: 341 AN: 3478

EpiCase AF: 0.222

EpiControl AF: 0.225

ClinVar

Significance: Benign

Submissions summary: Benign:9

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	Illumina Laboratory Services, Illumina	Jan 12, 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	Invitae	Feb 01, 2024	- -

not provided Benign:3

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.1686C>T (p.Ala562Ala) variant causes a synonymous change involving a non-conserved nucleotide with 4/5 splice prediction tools predicting no significant impact on splicing or ESE binding, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 20642/118716 (2070 homozygotes, 1/5, frequency: 0.1738772), 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. In addition, the variant has been indicated to co-occur with other pathogenic PTCH1 variants, c.2011_2012dup and c.3050_3051del, in affected individuals via publications. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2014

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. -

Holoprosencephaly 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	-0.77
Cadd	Benign	0.094
Dann	Benign	0.73

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: rs2066836; hg19: chr9-98238358; COSMIC: COSV59461212; COSMIC: COSV59461212;