rs357564

chr9-95447312-G-Achr9-95447312-G-Cchr9-95447312-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000264.5(PTCH1):c.3944C>T(p.Pro1315Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.353 in 1,612,980 control chromosomes in the GnomAD database, including 103,984 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1315H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.33 (8748 hom., cov: 32)
  • Exomes 𝑓: 0.36 (95236 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16 O:1
• Conservation: PhyloP100: 9.54

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PTCH1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0032435358).
• BP6: Variant 9-95447312-G-A is Benign according to our data. Variant chr9-95447312-G-A is described in ClinVar as [Benign]. Clinvar id is 41663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95447312-G-A is described in Lovd as [Benign]. Variant chr9-95447312-G-A is described in Lovd as [Likely_benign]. Variant chr9-95447312-G-A is described in Lovd as [Pathogenic].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.546 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH1	NM_000264.5	c.3944C>T	p.Pro1315Leu	missense_variant	23/24	ENST00000331920.11
PTCH1	NM_001083603.3	c.3941C>T	p.Pro1314Leu	missense_variant	23/24	ENST00000437951.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11	c.3944C>T	p.Pro1315Leu	missense_variant	23/24	5	NM_000264.5	A2
PTCH1	ENST00000437951.6	c.3941C>T	p.Pro1314Leu	missense_variant	23/24	5	NM_001083603.3

Frequencies

GnomAD3 genomes AF: 0.330 AC: 50147 AN: 151954 Hom.: 8752 Cov.: 32

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.468

Gnomad AMR AF: 0.387

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.564

Gnomad SAS AF: 0.472

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.337

Gnomad OTH AF: 0.338

GnomAD3 exomes AF: 0.389 AC: 95817 AN: 246178 Hom.: 19668 AF XY: 0.388 AC XY: 52207 AN XY: 134464

Gnomad AFR exome AF: 0.233

Gnomad AMR exome AF: 0.487

Gnomad ASJ exome AF: 0.320

Gnomad EAS exome AF: 0.563

Gnomad SAS exome AF: 0.447

Gnomad FIN exome AF: 0.406

Gnomad NFE exome AF: 0.339

Gnomad OTH exome AF: 0.369

GnomAD4 exome AF: 0.356 AC: 519565 AN: 1460908 Hom.: 95236 Cov.: 70 AF XY: 0.358 AC XY: 259922 AN XY: 726768

Gnomad4 AFR exome AF: 0.230

Gnomad4 AMR exome AF: 0.476

Gnomad4 ASJ exome AF: 0.315

Gnomad4 EAS exome AF: 0.583

Gnomad4 SAS exome AF: 0.451

Gnomad4 FIN exome AF: 0.409

Gnomad4 NFE exome AF: 0.338

Gnomad4 OTH exome AF: 0.358

GnomAD4 genome AF: 0.330 AC: 50158 AN: 152072 Hom.: 8748 Cov.: 32 AF XY: 0.338 AC XY: 25139 AN XY: 74320

Gnomad4 AFR AF: 0.232

Gnomad4 AMR AF: 0.387

Gnomad4 ASJ AF: 0.321

Gnomad4 EAS AF: 0.563

Gnomad4 SAS AF: 0.472

Gnomad4 FIN AF: 0.399

Gnomad4 NFE AF: 0.337

Gnomad4 OTH AF: 0.337

Alfa AF: 0.336 Hom.: 17485

Bravo AF: 0.326

TwinsUK AF: 0.328 AC: 1215

ALSPAC AF: 0.340 AC: 1309

ESP6500AA AF: 0.239 AC: 1009

ESP6500EA AF: 0.330 AC: 2752

ExAC AF: 0.380 AC: 45697

Asia WGS AF: 0.486 AC: 1685 AN: 3478

EpiCase AF: 0.337

EpiControl AF: 0.332

ClinVar

Significance: Benign

Submissions summary: Benign:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5 Other:1

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 29, 2016	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Gorlin syndrome Benign:4

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	Mar 06, 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	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -

not provided Benign:4

Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 29081410, 24728327, 27153395, 15888139, 22703879) -
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.3944C>T (p.Pro1315Leu) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a damaging outcome for this variant (SNPs&GO and MutationTaster not captured due to low reliability index). This variant was found in 44727/116034 control chromosomes (9126 homozygotes) at a frequency of 0.3854646, which significantly exceeds the estimated maximal expected allele frequency of a pathogenic PTCH1 variant (0.0000171), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

Holoprosencephaly 7 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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	Genome-Nilou Lab	Oct 25, 2021	- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.38	T;.;.;.;.;.;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.81	T;.;T;T;.;.;T
MetaRNN	Benign	0.0032	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;.;.;.;.;.;.
MutationTaster	Benign	4.5e-11	P;P;P;P;P;P;P
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N;N
REVEL	Uncertain	0.44
Sift	Uncertain	0.025	D;D;D;D;D;D;D
Sift4G	Uncertain	0.023	D;D;D;D;D;D;D
Polyphen		0.91	P;.;.;P;P;.;P
Vest4		0.57
MPC		0.40
ClinPred		0.027	T
GERP RS		4.8
Varity_R		0.21
gMVP		0.55

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: rs357564; hg19: chr9-98209594; COSMIC: COSV59463357;