NM_000264.5:c.884C>T

Variant names:

• chr9-95480451-G-A
• rs370755364
• NM_000264.5:c.884C>T
• PTCH1 p.Pro295Leu

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). PM2_SupportingPP3_ModerateBS2BP6

The NM_000264.5(PTCH1):c.884C>T (p.Pro295Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000714 (AC=115) in the gnomAD database across 1,611,624 control chromosomes, including 1 homozygote. The grpmax filtering allele frequency (95% CI) is 0.0000208. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.60). Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.P295= (synonymous): Likely_benign (ClinVar VariationId 1764907, 1 star); p.P295= (synonymous): Likely_benign (ClinVar VariationId 2916215, 2 stars); p.P295S: Uncertain_significance (ClinVar VariationId 2633768, 2 stars); p.P295T: Uncertain_significance (ClinVar VariationId 4862716, 1 star)

• Frequency:
  • Genomes: 𝑓 0.000060 (1 hom., cov: 31)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 9.60
• Publications: 4 publications found

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]

PTCH1 Gene-Disease associations (from GenCC):

• basal cell nevus syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia
• holoprosencephaly 7

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• nevoid basal cell carcinoma syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, ClinGen
• exstrophy-epispadias complex

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• holoprosencephaly

  Inheritance: AD Classification: LIMITED Submitted by: Illumina, ClinGen

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000208 — borderline rare for AD/XL gene (threshold 0.0001) — PM2 supporting.
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
	BP6Reputable source reports benign		ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).
	BS2Observed in healthy adult		Pure AD gene with cumulative gnomAD AC ≥5 — observed in healthy adults (BS2); GnomAD homozygous count = 1.; Very high cumulative gnomAD AC = 115 (any gene).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000264.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PTCH1 NM_000264.5	MANE Select	c.884C>T p.Pro295Leu	missense	Exon 6 of 24	Prot: NP_000255.2 UniProt:
	PTCH1 NM_001083603.3	MANE Plus Clinical	c.881C>T p.Pro294Leu	missense	Exon 6 of 24	Prot: NP_001077072.1 UniProt:
	PTCH1 NM_001354918.2		c.884C>T p.Pro295Leu	missense	Exon 6 of 23	Prot: NP_001341847.1 UniProt:

PTCH1 NM_000264.5

MANE Select

HGVSc / HGVSpc.884C>Tp.Pro295Leu

Exon rankExon 6 of 24

missense

Prot: NP_000255.2UniProt: Q13635-1

PTCH1 NM_001083603.3

MANE Plus Clinical

HGVSc / HGVSpc.881C>Tp.Pro294Leu

Exon rankExon 6 of 24

missense

Prot: NP_001077072.1UniProt: Q13635-2

PTCH1 NM_001354918.2

HGVSc / HGVSpc.884C>Tp.Pro295Leu

Exon rankExon 6 of 23

missense

Prot: NP_001341847.1UniProt: A0A1W5YLI7

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PTCH1 ENST00000331920.11	TSL:5MANE Select	c.884C>T p.Pro295Leu	missense	Exon 6 of 24	Prot: ENSP00000332353.6 UniProt:
	PTCH1 ENST00000437951.6	TSL:5MANE Plus Clinical	c.881C>T p.Pro294Leu	missense	Exon 6 of 24	Prot: ENSP00000389744.2 UniProt:
	PTCH1 ENST00000429896.6	TSL:1	c.431C>T p.Pro144Leu	missense	Exon 6 of 24	Prot: ENSP00000414823.2 UniProt:

PTCH1 ENST00000331920.11

TSL:5MANE Select

HGVSc / HGVSpc.884C>Tp.Pro295Leu

Exon rankExon 6 of 24

missense

Prot: ENSP00000332353.6UniProt: Q13635-1

PTCH1 ENST00000437951.6

TSL:5MANE Plus Clinical

HGVSc / HGVSpc.881C>Tp.Pro294Leu

Exon rankExon 6 of 24

missense

Prot: ENSP00000389744.2UniProt: Q13635-2

PTCH1 ENST00000429896.6

TSL:1

HGVSc / HGVSpc.431C>Tp.Pro144Leu

Exon rankExon 6 of 24

missense

Prot: ENSP00000414823.2UniProt: Q13635-4

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000601	AC:9	Hom:1	AN:149772	Cov:31
GnomAD2 exomes	AF: 0.0000994	AC:25	Hom:	AN:251404	Cov:
GnomAD4 exome	AF: 0.0000725	AC:106	Hom:0	AN:1461852	Cov:31
GnomAD4 genome	AF: 0.0000601	AC:9	Hom:1	AN:149772	Cov:31
TOPMed (Bravo)	AF: 0.0000604	AC:16	Hom:1	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000243	AC:11	Hom:0	AN:45216	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	AF: 0.0000769	AC:1	Hom:	AN:13006	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000352	1	28420	0.0000347	1	28844
Epi25(Epilepsy)	0.00	0	41958	0.0000299	2	66888
SCHEMA(Schizophrenia)	0.0000329	4	121744	0.0000683	13	190462

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Gorlin syndrome (2)
-	1	1	Holoprosencephaly 7;C2751544:Basal cell carcinoma, susceptibility to, 1;CN376810:Basal cell nevus syndrome 1 (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	Holoprosencephaly 7 (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	24
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Pathogenic	0.46
GPN-Star LLR	N/A	-8.5
GPN-Star score	N/A	8.5
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Pathogenic	0.95	D
Mutation Taster	N/A	5/95	disease causing
MutationAssessor	Pathogenic	3.0	M
PhyloP100	Pathogenic	9.6
popEVE	Benign	-3.5
PrimateAI	Pathogenic	0.84	D
PromoterAI	N/A	0.0063	Neutral
PROVEAN	Pathogenic	-9.5	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.86
VESM-3B	Benign	-8.3

Showing 31 of 31 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs370755364;

hg19: chr9-98242733;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar