rs2066835

chr9-95458040-A-Cchr9-95458040-A-T

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.3141T>G(p.Leu1047=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,614,126 control chromosomes in the GnomAD database, including 872 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. L1047L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.038 (293 hom., cov: 33)
  • Exomes 𝑓: 0.0096 (579 hom.)
• Consequence: PTCH1 NM_000264.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.132

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=-0.58).
• BP6: Variant 9-95458040-A-C is Benign according to our data. Variant chr9-95458040-A-C is described in ClinVar as [Benign]. Clinvar id is 255681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.132 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH1	NM_000264.5	c.3141T>G	p.Leu1047=	synonymous_variant	18/24	ENST00000331920.11
PTCH1	NM_001083603.3	c.3138T>G	p.Leu1046=	synonymous_variant	18/24	ENST00000437951.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11	c.3141T>G	p.Leu1047=	synonymous_variant	18/24	5	NM_000264.5	A2
PTCH1	ENST00000437951.6	c.3138T>G	p.Leu1046=	synonymous_variant	18/24	5	NM_001083603.3

Frequencies

GnomAD3 genomes AF: 0.0376 AC: 5716 AN: 152164 Hom.: 293 Cov.: 33

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0971

Gnomad SAS AF: 0.0484

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.0229

GnomAD3 exomes AF: 0.0215 AC: 5393 AN: 251214 Hom.: 248 AF XY: 0.0205 AC XY: 2783 AN XY: 135814

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.00497

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.101

Gnomad SAS exome AF: 0.0434

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00123

Gnomad OTH exome AF: 0.00929

GnomAD4 exome AF: 0.00956 AC: 13973 AN: 1461844 Hom.: 579 Cov.: 32 AF XY: 0.0101 AC XY: 7345 AN XY: 727216

Gnomad4 AFR exome AF: 0.117

Gnomad4 AMR exome AF: 0.00584

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.0944

Gnomad4 SAS exome AF: 0.0427

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00117

Gnomad4 OTH exome AF: 0.0161

GnomAD4 genome AF: 0.0376 AC: 5728 AN: 152282 Hom.: 293 Cov.: 33 AF XY: 0.0380 AC XY: 2827 AN XY: 74464

Gnomad4 AFR AF: 0.112

Gnomad4 AMR AF: 0.0123

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0974

Gnomad4 SAS AF: 0.0486

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00141

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0149 Hom.: 60

Bravo AF: 0.0415

Asia WGS AF: 0.0610 AC: 210 AN: 3478

EpiCase AF: 0.00180

EpiControl AF: 0.00119

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 specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 28, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 24, 2016	Variant summary: The c.3141T>C (p.Leu1047=) in PTCH1 gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.0239 (2894/120918 chrs tested), predominantly in individuals of African origin (0.1145; 1179/10292 control chrs) including numerous homozygous occurrences. This frequency exceeds the maximal expected frequency of a pathogenic allele (0.00007) in this gene. The variant of interest was cited as Polymorphism in published reports (Sun, 2008 and Musani, 2013). Taking together, the variant was classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 01, 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 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	-0.58
Cadd	Benign	5.9
Dann	Benign	0.67

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: rs2066835; hg19: chr9-98220322; COSMIC: COSV59476925;