rs62637631

chr9-95447176-G-Achr9-95447176-G-Cchr9-95447176-G-T

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.4080C>T(p.Ser1360=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00622 in 1,613,082 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1360S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0041 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (34 hom.)
• Consequence: PTCH1 NM_000264.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.0740

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=-0.63).
• BP6: Variant 9-95447176-G-A is Benign according to our data. Variant chr9-95447176-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 92698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95447176-G-A is described in Lovd as [Benign]. Variant chr9-95447176-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.074 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00406 (618/152360) while in subpopulation NFE AF= 0.00709 (482/68028). AF 95% confidence interval is 0.00656. There are 2 homozygotes in gnomad4. There are 294 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 618 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH1	NM_000264.5	c.4080C>T	p.Ser1360=	synonymous_variant	23/24	ENST00000331920.11
PTCH1	NM_001083603.3	c.4077C>T	p.Ser1359=	synonymous_variant	23/24	ENST00000437951.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11	c.4080C>T	p.Ser1360=	synonymous_variant	23/24	5	NM_000264.5	A2
PTCH1	ENST00000437951.6	c.4077C>T	p.Ser1359=	synonymous_variant	23/24	5	NM_001083603.3

Frequencies

GnomAD3 genomes AF: 0.00406 AC: 618 AN: 152242 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00707

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00397 AC: 981 AN: 246966 Hom.: 3 AF XY: 0.00390 AC XY: 524 AN XY: 134468

Gnomad AFR exome AF: 0.000980

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.000603

Gnomad EAS exome AF: 0.000383

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.00194

Gnomad NFE exome AF: 0.00715

Gnomad OTH exome AF: 0.00396

GnomAD4 exome AF: 0.00645 AC: 9423 AN: 1460722 Hom.: 34 Cov.: 30 AF XY: 0.00625 AC XY: 4543 AN XY: 726670

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00244

Gnomad4 ASJ exome AF: 0.000919

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.000870

Gnomad4 FIN exome AF: 0.00208

Gnomad4 NFE exome AF: 0.00791

Gnomad4 OTH exome AF: 0.00417

GnomAD4 genome AF: 0.00406 AC: 618 AN: 152360 Hom.: 2 Cov.: 32 AF XY: 0.00395 AC XY: 294 AN XY: 74504

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.00709

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00531 Hom.: 0

Bravo AF: 0.00399

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00703

EpiControl AF: 0.00818

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 12, 2023	- -
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.4080C>T (p.Ser1360Ser) variant causes a synonymous change involving a non-conserved nucleotide with 5/5 splice prediction tools predicting no significant affect on splicing. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 468/116042 (1/247, 2 homozygotes), which significantly exceeds the expected allele frequency for a pathogenic PTCH1 variant of 1/58479, suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories have cited the variant as "benign." Therefore, the variant of interest has been classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PTCH1: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 19, 2021	- -
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	Eurofins Ntd Llc (ga)	Jul 30, 2013	- -

Gorlin syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	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:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 11, 2016	This alteration is classified as likely 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	Nov 06, 2020	- -

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	6.0
Dann	Benign	0.72

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: rs62637631; hg19: chr9-98209458; COSMIC: COSV59496118;