rs786204147

chr9-95508325-G-Cchr9-95508325-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_000264.5(PTCH1):c.37C>G(p.Arg13Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000671 in 1,329,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R13C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (0 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:6
• Conservation: PhyloP100: -1.28

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 -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PTCH1
• BP4: Computational evidence support a benign effect (MetaRNN=0.050979435).
• BP6: Variant 9-95508325-G-C is Benign according to our data. Variant chr9-95508325-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 188208.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=4, Benign=2}. Variant chr9-95508325-G-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 96 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH1	NM_000264.5	c.37C>G	p.Arg13Gly	missense_variant	1/24	ENST00000331920.11
PTCH1	NM_001083603.3	c.199-1726C>G		intron_variant		ENST00000437951.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11	c.37C>G	p.Arg13Gly	missense_variant	1/24	5	NM_000264.5	A2
PTCH1	ENST00000437951.6	c.199-1726C>G		intron_variant		5	NM_001083603.3

Frequencies

GnomAD3 genomes AF: 0.000638 AC: 96 AN: 150494 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000786

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000934

Gnomad OTH AF: 0.00145

GnomAD3 exomes AF: 0.000785 AC: 7 AN: 8920 Hom.: 0 AF XY: 0.000968 AC XY: 5 AN XY: 5166

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00146

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000676 AC: 797 AN: 1179380 Hom.: 0 Cov.: 33 AF XY: 0.000714 AC XY: 408 AN XY: 571782

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000876

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00164

Gnomad4 SAS exome AF: 0.000173

Gnomad4 FIN exome AF: 0.0000637

Gnomad4 NFE exome AF: 0.000730

Gnomad4 OTH exome AF: 0.000459

GnomAD4 genome AF: 0.000637 AC: 96 AN: 150606 Hom.: 0 Cov.: 32 AF XY: 0.000652 AC XY: 48 AN XY: 73574

Gnomad4 AFR AF: 0.000146

Gnomad4 AMR AF: 0.00132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000788

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000934

Gnomad4 OTH AF: 0.00144

Alfa AF: 0.0000694 Hom.: 0

Bravo AF: 0.000812

ExAC AF: 0.0000735 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2021	Reported previously in an individual with breast cancer (Chan et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30093976) -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PTCH1: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 13, 2022	- -

Gorlin syndrome Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 01, 2019	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	Jan 04, 2022	- -

Gorlin syndrome;C1835820:Holoprosencephaly 7;C2751544:Basal cell carcinoma, susceptibility to, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Holoprosencephaly 7 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

PTCH1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 29, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	19
Dann	Benign	0.83
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.45	T
M_CAP	Pathogenic	0.86	D
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	-0.34	N
MutationTaster	Benign	1.0	D;D;D;D;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.26
Sift	Benign	0.65	T
Sift4G	Benign	0.48	T
Polyphen		0.0	B
Vest4		0.067
MutPred		0.21		Gain of relative solvent accessibility (P = 0.0166);
MVP		0.29
MPC		0.70
ClinPred		0.029	T
GERP RS		1.4
Varity_R		0.14
gMVP		0.26

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: rs779791579; hg19: chr9-98270607;