rs547954117

Positions:

• chr9-95467406-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 2P and 18B. PP2 PP3 BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000264.5(PTCH1):​c.2270T>C​(p.Phe757Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000168 in 1,614,180 control chromosomes in the GnomAD database, including 4 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. F757F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (4 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 7.02

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]

LOC100507346 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PTCH1
• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, M_CAP, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.098285824).
• BP6: Variant 9-95467406-A-G is Benign according to our data. Variant chr9-95467406-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 237468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000985 (15/152318) while in subpopulation SAS AF= 0.0029 (14/4826). AF 95% confidence interval is 0.00175. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH1	NM_000264.5	c.2270T>C	p.Phe757Ser	missense_variant	15/24	ENST00000331920.11
PTCH1	NM_001083603.3	c.2267T>C	p.Phe756Ser	missense_variant	15/24	ENST00000437951.6
LOC100507346	NR_038982.1	n.556A>G		non_coding_transcript_exon_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11	c.2270T>C	p.Phe757Ser	missense_variant	15/24	5	NM_000264.5	A2
PTCH1	ENST00000437951.6	c.2267T>C	p.Phe756Ser	missense_variant	15/24	5	NM_001083603.3

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000350 AC: 88 AN: 251124 Hom.: 0 AF XY: 0.000456 AC XY: 62 AN XY: 135824

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: 0.00274

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000175 AC: 256 AN: 1461862 Hom.: 4 Cov.: 33 AF XY: 0.000234 AC XY: 170 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00265

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74488

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.000436 AC: 53

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gorlin syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Aug 19, 2020	The c.2270T>C (p.Phe757Ser) missense variant has a frequency of 0.0003504 (88 of 251,124 alleles) in gnomAD v2.1.1 with a maximum allele frequency of 0.002744 (84 of 30,614) in the South Asian population (http://gnomad.broadinstitute.org). This exceeds the expected incidence of a pathogenic variant causing Gorlin syndrome, in which the prevalence is estimated to be 1 in 31,000 people (0.003%) (BS1). Six of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), however this has not been confirmed in functional assays. To our knowledge, this variant has not been reported in individuals with Gorlin syndrome (internal data and literature review). In summary, this variant meets criteria to be classified as likely benign as the population frequency is not consistent with disease. ACMG/AMP criteria met: BS1, PP3. -
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. -

PTCH1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 18, 2019

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). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2024

PTCH1: PP3, BS1 -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2020

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 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
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.;.;.;.;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T;.;T;T;.;.;T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.098	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Uncertain	2.5	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.8	D;D;D;D;D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.016	D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D
Polyphen		0.77	P;.;.;D;D;.;D
Vest4		0.89
MutPred		0.79		Loss of stability (P = 0.0731);.;.;.;.;.;.;
MVP		0.75
MPC		1.8
ClinPred		0.17	T
GERP RS		4.3
Varity_R		0.87
gMVP		0.87

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: rs547954117; hg19: chr9-98229688;