rs2066830

Positions:

• chr9-95476121-G-A
• chr9-95476121-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000264.5(PTCH1):​c.1641C>T​(p.Ser547Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,613,520 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (9 hom., cov: 32)
  • Exomes 𝑓: 0.012 (116 hom.)
• Consequence: PTCH1 NM_000264.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.910

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 9-95476121-G-A is Benign according to our data. Variant chr9-95476121-G-A is described in ClinVar as [Benign]. Clinvar id is 132700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95476121-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.91 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00784 (1194/152322) while in subpopulation NFE AF= 0.0128 (870/68026). AF 95% confidence interval is 0.0121. There are 9 homozygotes in gnomad4. There are 574 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1194 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.1641C>T	p.Ser547Ser	synonymous_variant	12/24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.1638C>T	p.Ser546Ser	synonymous_variant	12/24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.1641C>T	p.Ser547Ser	synonymous_variant	12/24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.1638C>T	p.Ser546Ser	synonymous_variant	12/24	5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes AF: 0.00784 AC: 1194 AN: 152204 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00273

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00885

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0128

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00784 AC: 1957 AN: 249624 Hom.: 14 AF XY: 0.00797 AC XY: 1076 AN XY: 134956

Gnomad AFR exome AF: 0.00224

Gnomad AMR exome AF: 0.00255

Gnomad ASJ exome AF: 0.000597

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000987

Gnomad FIN exome AF: 0.0107

Gnomad NFE exome AF: 0.0137

Gnomad OTH exome AF: 0.00771

GnomAD4 exome AF: 0.0116 AC: 16959 AN: 1461198 Hom.: 116 Cov.: 34 AF XY: 0.0111 AC XY: 8103 AN XY: 726872

Gnomad4 AFR exome AF: 0.00194

Gnomad4 AMR exome AF: 0.00269

Gnomad4 ASJ exome AF: 0.000651

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000163

Gnomad4 FIN exome AF: 0.0109

Gnomad4 NFE exome AF: 0.0141

Gnomad4 OTH exome AF: 0.00830

GnomAD4 genome AF: 0.00784 AC: 1194 AN: 152322 Hom.: 9 Cov.: 32 AF XY: 0.00771 AC XY: 574 AN XY: 74484

Gnomad4 AFR AF: 0.00272

Gnomad4 AMR AF: 0.00490

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00885

Gnomad4 NFE AF: 0.0128

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00975 Hom.: 2

Bravo AF: 0.00727

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0117

EpiControl AF: 0.0112

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 30, 2016	Variant summary: The PTCH1 c.1641C>T (p.Ser547Ser) 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. 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 994/110038 control chromosomes (7 homozygotes) at a frequency of 0.0090332, which is approximately 527 times the estimated maximal expected allele frequency of a pathogenic PTCH1 variant (0.0000171), suggesting this variant is likely a benign polymorphism. In addition, one clinical diagnostic laboratory classified this variant as benign. Taken together, this variant 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 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PTCH1: BP4, BP7, BS1, BS2 -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 23, 2021	- -

Gorlin syndrome Benign:2

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 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. -

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	-0.34
CADD	Benign	7.8
DANN	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2066830; hg19: chr9-98238403; COSMIC: COSV59461249; COSMIC: COSV59461249;