rs587780708

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_000264.5(PTCH1):c.56G>T(p.Gly19Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000213 in 1,407,284 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. G19D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

PTCH1
NM_000264.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.664

Publications

0 publications found

Variant links:

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: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21601322).

BP6

Variant 9-95508306-C-A is Benign according to our data. Variant chr9-95508306-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 135905.

BS2

High AC in GnomAdExome4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5 link	c.56G>T	p.Gly19Val	missense_variant	Exon 1 of 24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3 link	c.199-1707G>T		intron_variant	Intron 1 of 23	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11 link	c.56G>T	p.Gly19Val	missense_variant	Exon 1 of 24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6 link	c.199-1707G>T		intron_variant	Intron 1 of 23	5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151398

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000231

AC:

AN:

1255886

Hom.:

Cov.:

AF XY:

0.0000228

AC XY:

AN XY:

613042

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24584

American (AMR)

AF:

0.00

AC:

AN:

14940

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17828

East Asian (EAS)

AF:

0.00

AC:

AN:

29184

South Asian (SAS)

AF:

0.0000172

AC:

AN:

58114

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36282

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3578

European-Non Finnish (NFE)

AF:

0.0000226

AC:

AN:

1019782

Other (OTH)

AF:

0.0000969

AC:

AN:

51594

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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

AF:

0.00000661

AC:

AN:

151398

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73904

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41378

American (AMR)

AF:

0.00

AC:

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3454

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67698

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Feb 20, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is denoted PTCH1 c.56G>T at the cDNA level, p.Gly19Val (G19V) at the protein level, and results in the change of a Glycine to a Valine (GGC>GTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PTCH1 Gly19Val occurs at a position that has low coverage in the NHLBI Exome Sequencing Project, therefore we cannot assess frequency in the general population. Since Glycine and Valine share similar properties, this is considered a conservative amino acid substitution. PTCH1 Gly19Val occurs at a position that is not conserved and is located in cytoplasmic topological domain and in a glycine-rich region of compositional bias (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether PTCH1 Gly19Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Jul 31, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G19V variant (also known as c.56G>T), located in coding exon 1 of the PTCH1 gene, results from a G to T substitution at nucleotide position 56. The glycine at codon 19 is replaced by valine, an amino acid with dissimilar properties. This amino acid position is not well conserved on limited sequence alignment. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Gorlin syndrome

Benign:1

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.039

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.20

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.43

M_CAP

Pathogenic

0.62

MetaRNN

Benign

0.22

MetaSVM

Uncertain

0.057

MutationAssessor

Benign

0.0

PhyloP100

0.66

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.25

REVEL

Uncertain

0.35

Sift

Uncertain

0.019

Sift4G

Uncertain

0.034

Polyphen

0.83

Vest4

0.11

MutPred

0.33

Gain of sheet (P = 0.0043);

MVP

0.33

MPC

1.6

ClinPred

0.25

GERP RS

2.5

PromoterAI

0.020

Neutral

(source)

Varity_R

0.18

gMVP

0.42

Mutation Taster

=89/11

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over