rs2227968

Positions:

• chr9-95447411-G-A
• chr9-95447411-G-C
• chr9-95447411-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000264.5(PTCH1):​c.3845C>T​(p.Pro1282Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00165 in 1,605,002 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict 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. P1282R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0088 (25 hom., cov: 33)
  • Exomes 𝑓: 0.00091 (26 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: 5.19

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=0.0031888783).
• BP6: Variant 9-95447411-G-A is Benign according to our data. Variant chr9-95447411-G-A is described in ClinVar as [Benign]. Clinvar id is 41661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95447411-G-A is described in Lovd as [Benign]. Variant chr9-95447411-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00877 (1336/152294) while in subpopulation AFR AF= 0.0302 (1256/41558). AF 95% confidence interval is 0.0288. There are 25 homozygotes in gnomad4. There are 650 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1336 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH1	NM_000264.5	c.3845C>T	p.Pro1282Leu	missense_variant	23/24	ENST00000331920.11
PTCH1	NM_001083603.3	c.3842C>T	p.Pro1281Leu	missense_variant	23/24	ENST00000437951.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11	c.3845C>T	p.Pro1282Leu	missense_variant	23/24	5	NM_000264.5	A2
PTCH1	ENST00000437951.6	c.3842C>T	p.Pro1281Leu	missense_variant	23/24	5	NM_001083603.3

Frequencies

GnomAD3 genomes AF: 0.00880 AC: 1339 AN: 152176 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.0304

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00224 AC: 541 AN: 241766 Hom.: 12 AF XY: 0.00178 AC XY: 234 AN XY: 131790

Gnomad AFR exome AF: 0.0306

Gnomad AMR exome AF: 0.00160

Gnomad ASJ exome AF: 0.00105

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000546

Gnomad OTH exome AF: 0.00119

GnomAD4 exome AF: 0.000905 AC: 1315 AN: 1452708 Hom.: 26 Cov.: 33 AF XY: 0.000803 AC XY: 580 AN XY: 722064

Gnomad4 AFR exome AF: 0.0291

Gnomad4 AMR exome AF: 0.00185

Gnomad4 ASJ exome AF: 0.00132

Gnomad4 EAS exome AF: 0.000152

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.0000196

Gnomad4 NFE exome AF: 0.0000903

Gnomad4 OTH exome AF: 0.00195

GnomAD4 genome AF: 0.00877 AC: 1336 AN: 152294 Hom.: 25 Cov.: 33 AF XY: 0.00873 AC XY: 650 AN XY: 74474

Gnomad4 AFR AF: 0.0302

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00159 Hom.: 6

Bravo AF: 0.00963

ESP6500AA AF: 0.0239 AC: 103

ESP6500EA AF: 0.000235 AC: 2

ExAC AF: 0.00265 AC: 321

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4 Other:1

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 26, 2021	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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: 24728327) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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 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	Invitae	Feb 01, 2024	- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 28, 2015

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
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.27	T;.;.;.;.;.;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D;.;D;D;.;.;D
MetaRNN	Benign	0.0032	T;T;T;T;T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.1	M;.;.;.;.;.;.
MutationTaster	Benign	0.99	N;N;N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.50	N;N;N;N;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.068	T;T;T;T;T;T;T
Sift4G	Benign	0.27	T;T;T;T;T;T;T
Polyphen		0.38	B;.;.;B;B;.;P
Vest4		0.49
MVP		0.57
MPC		0.083
ClinPred		0.012	T
GERP RS		2.9
Varity_R		0.074
gMVP		0.29

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: rs2227968; hg19: chr9-98209693; COSMIC: COSV105897831;