rs201595274

chr9-95447417-G-Achr9-95447417-G-Cchr9-95447417-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.3839C>T(p.Ser1280Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000705 in 1,602,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1280W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.653

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=0.0036492944).
• BP6: Variant 9-95447417-G-A is Benign according to our data. Variant chr9-95447417-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 415469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95447417-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000158 (24/152306) while in subpopulation EAS AF= 0.00387 (20/5170). AF 95% confidence interval is 0.00256. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH1	NM_000264.5	c.3839C>T	p.Ser1280Leu	missense_variant	23/24	ENST00000331920.11
PTCH1	NM_001083603.3	c.3836C>T	p.Ser1279Leu	missense_variant	23/24	ENST00000437951.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11	c.3839C>T	p.Ser1280Leu	missense_variant	23/24	5	NM_000264.5	A2
PTCH1	ENST00000437951.6	c.3836C>T	p.Ser1279Leu	missense_variant	23/24	5	NM_001083603.3

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000230 AC: 55 AN: 239534 Hom.: 0 AF XY: 0.000145 AC XY: 19 AN XY: 130612

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00291

Gnomad SAS exome AF: 0.0000675

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000916

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000614 AC: 89 AN: 1450536 Hom.: 0 Cov.: 33 AF XY: 0.0000527 AC XY: 38 AN XY: 720830

Gnomad4 AFR exome AF: 0.0000303

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00167

Gnomad4 SAS exome AF: 0.0000351

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.0000835

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74474

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00387

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.000215 AC: 26

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 22, 2017	Variant summary: The PTCH1 c.3839C>T (p.Ser1280Leu) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict benign outcome for this variant. This variant was found in 25/113926 control chromosomes from ExAC at a frequency of 0.0002194, which is approximately 13 times 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 in ClinVar have classified this variant as likely benign. To our knowledge, this variant has not been reported in affected individuals in literature, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	PTCH1: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Gorlin syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 10, 2024	- -
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	Oct 11, 2018	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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 03, 2021	- -

Ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Jan 01, 2022

- -

Holoprosencephaly 7 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	11
Dann	Benign	0.93
DEOGEN2	Benign	0.33	T;.;.;.;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.79	T;.;T;T;.;.;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.0036	T;T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.5	L;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.44	T;T;T;T;T;T;T
Sift4G	Benign	0.28	T;T;T;T;T;T;T
Polyphen		0.0	B;.;.;B;B;.;B
Vest4		0.12
MVP		0.42
MPC		0.073
ClinPred		0.0074	T
GERP RS		-0.33
Varity_R		0.055
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201595274; hg19: chr9-98209699;