NM_000264.5:c.3346G>C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4BP6BS2

The NM_000264.5(PTCH1):c.3346G>C(p.Val1116Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1116M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

PTCH1
NM_000264.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 2.94

Publications

3 publications found

Variant links:

COSMIC-nc: COSV59480459

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 Submitted by: G2P
holoprosencephaly 7
Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
nevoid basal cell carcinoma syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
holoprosencephaly
Inheritance: AD Classification: LIMITED Submitted by: Illumina

PTCH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.35407692).

BP6

Variant 9-95453581-C-G is Benign according to our data. Variant chr9-95453581-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 2154676. Variant chr9-95453581-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 2154676. Variant chr9-95453581-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 2154676. Variant chr9-95453581-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 2154676. Variant chr9-95453581-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 2154676. Variant chr9-95453581-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 2154676. Variant chr9-95453581-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 2154676. Variant chr9-95453581-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 2154676. Variant chr9-95453581-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 2154676. Variant chr9-95453581-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 2154676. Variant chr9-95453581-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 2154676. Variant chr9-95453581-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 2154676. Variant chr9-95453581-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 2154676. Variant chr9-95453581-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 2154676.

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5 link	c.3346G>C	p.Val1116Leu	missense_variant	Exon 20 of 24	ENST00000331920.11	NP_000255.2	Q13635-1
PTCH1	NM_001083603.3 link	c.3343G>C	p.Val1115Leu	missense_variant	Exon 20 of 24	ENST00000437951.6	NP_001077072.1	Q13635-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11 link	c.3346G>C	p.Val1116Leu	missense_variant	Exon 20 of 24	5	NM_000264.5	ENSP00000332353.6		Q13635-1
PTCH1	ENST00000437951.6 link	c.3343G>C	p.Val1115Leu	missense_variant	Exon 20 of 24	5	NM_001083603.3	ENSP00000389744.2		Q13635-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

250984

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461750

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53278

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1

Jun 20, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.V1116L variant (also known as c.3346G>C), located in coding exon 20 of the PTCH1 gene, results from a G to C substitution at nucleotide position 3346. The valine at codon 1116 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Gorlin syndrome

Benign:1

Oct 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.058

BayesDel_noAF

Uncertain

0.010

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

T;.;.;.;.;.;.

Eigen

Benign

0.030

Eigen_PC

Benign

0.066

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.82

T;.;T;T;.;.;T

M_CAP

Uncertain

0.090

MetaRNN

Benign

0.35

T;T;T;T;T;T;T

MetaSVM

Uncertain

0.30

MutationAssessor

Benign

0.55

N;.;.;.;.;.;.

PhyloP100

2.9

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.79

N;N;N;N;N;N;N

REVEL

Uncertain

0.61

Sift

Benign

0.33

T;T;T;T;T;T;T

Sift4G

Benign

0.30

T;T;T;T;T;T;T

Polyphen

0.80

P;.;.;P;P;.;P

Vest4

0.40

MutPred

0.52

Loss of ubiquitination at K1111 (P = 0.1264);.;.;.;.;.;.;

MVP

0.69

MPC

0.58

ClinPred

0.41

GERP RS

3.3

Varity_R

0.21

gMVP

0.74

Mutation Taster

=61/39

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over