rs1805154

Positions:

• chr9-95481960-T-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.735A>G​(p.Thr245Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0303 in 1,610,610 control chromosomes in the GnomAD database, including 953 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (60 hom., cov: 32)
  • Exomes 𝑓: 0.031 (893 hom.)
• Consequence: PTCH1 NM_000264.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.202

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=-0.63).
• BP6: Variant 9-95481960-T-C is Benign according to our data. Variant chr9-95481960-T-C is described in ClinVar as [Benign]. Clinvar id is 132726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95481960-T-C is described in Lovd as [Benign]. Variant chr9-95481960-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.202 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0219 (3331/152328) while in subpopulation NFE AF= 0.0353 (2404/68018). AF 95% confidence interval is 0.0342. There are 60 homozygotes in gnomad4. There are 1577 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3331 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.735A>G	p.Thr245Thr	synonymous_variant	5/24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.732A>G	p.Thr244Thr	synonymous_variant	5/24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.735A>G	p.Thr245Thr	synonymous_variant	5/24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.732A>G	p.Thr244Thr	synonymous_variant	5/24	5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes AF: 0.0219 AC: 3331 AN: 152210 Hom.: 60 Cov.: 32

Gnomad AFR AF: 0.00547

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0178

Gnomad ASJ AF: 0.0372

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.0195

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0353

Gnomad OTH AF: 0.0234

GnomAD3 exomes AF: 0.0224 AC: 5632 AN: 251356 Hom.: 99 AF XY: 0.0227 AC XY: 3088 AN XY: 135846

Gnomad AFR exome AF: 0.00486

Gnomad AMR exome AF: 0.0162

Gnomad ASJ exome AF: 0.0387

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00532

Gnomad FIN exome AF: 0.0182

Gnomad NFE exome AF: 0.0340

Gnomad OTH exome AF: 0.0287

GnomAD4 exome AF: 0.0311 AC: 45397 AN: 1458282 Hom.: 893 Cov.: 30 AF XY: 0.0305 AC XY: 22138 AN XY: 725732

Gnomad4 AFR exome AF: 0.00470

Gnomad4 AMR exome AF: 0.0165

Gnomad4 ASJ exome AF: 0.0376

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00579

Gnomad4 FIN exome AF: 0.0180

Gnomad4 NFE exome AF: 0.0362

Gnomad4 OTH exome AF: 0.0277

GnomAD4 genome AF: 0.0219 AC: 3331 AN: 152328 Hom.: 60 Cov.: 32 AF XY: 0.0212 AC XY: 1577 AN XY: 74482

Gnomad4 AFR AF: 0.00546

Gnomad4 AMR AF: 0.0178

Gnomad4 ASJ AF: 0.0372

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.0195

Gnomad4 NFE AF: 0.0353

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.0293 Hom.: 31

Bravo AF: 0.0219

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0357

EpiControl AF: 0.0384

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Mar 31, 2021	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:4

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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 24, 2016	Variant summary: The PTCH1 c.735A>G (p.Thr245Thr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant along with 5/5 splice site prediction tools predicting the variant not to have an impact on splicing. This variant was found in 2760/120306 control chromosomes (42 homozygotes) at a frequency of 0.0229415, which is approximately 1339 times the estimated maximal expected allele frequency of a pathogenic PTCH1 variant (0.0000171), suggesting this variant is likely a benign polymorphism. One clinical diagnostic laboratory classified this variant as Benign. Additionally, the variant has been reported in the literature as a polymorphism (Musani_Gene_2013).Taken together and based on the high frequency in the general population, this variant is classified as Benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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	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. -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 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	-0.63
CADD	Benign	5.7
DANN	Benign	0.48

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: rs1805154; hg19: chr9-98244242; COSMIC: COSV59479599; COSMIC: COSV59479599;