NM_000264.5:c.4219G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000264.5(PTCH1):c.4219G>A(p.Gly1407Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,614,180 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. G1407G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

PTCH1
NM_000264.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: 2.51

Publications

4 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04667017).

BP6

Variant 9-95447037-C-T is Benign according to our data. Variant chr9-95447037-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 135106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95447037-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 135106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95447037-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 135106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95447037-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 135106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95447037-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 135106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95447037-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 135106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95447037-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 135106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95447037-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 135106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95447037-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 135106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95447037-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 135106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95447037-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 135106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95447037-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 135106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95447037-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 135106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95447037-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 135106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5 link	c.4219G>A	p.Gly1407Ser	missense_variant	Exon 23 of 24	ENST00000331920.11	NP_000255.2	Q13635-1
PTCH1	NM_001083603.3 link	c.4216G>A	p.Gly1406Ser	missense_variant	Exon 23 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.4219G>A	p.Gly1407Ser	missense_variant	Exon 23 of 24	5	NM_000264.5	ENSP00000332353.6		Q13635-1
PTCH1	ENST00000437951.6 link	c.4216G>A	p.Gly1406Ser	missense_variant	Exon 23 of 24	5	NM_001083603.3	ENSP00000389744.2		Q13635-2

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000103

AC:

AN:

251368

AF XY:

0.000103

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000164

AC:

240

AN:

1461872

Hom.:

Cov.:

AF XY:

0.000155

AC XY:

113

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.000134

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000176

AC:

AN:

39700

South Asian (SAS)

AF:

0.000243

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000176

AC:

196

AN:

1112012

Other (OTH)

AF:

0.000132

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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:

0.000105

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41566

American (AMR)

AF:

0.000261

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.000198

Hom.:

Bravo

AF:

0.000170

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Gorlin syndrome

Benign:2

Aug 22, 2023

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:2

Jan 04, 2022

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

May 16, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:1

Jun 26, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

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

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.037

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.87

D;.;D;D;.;.;D

M_CAP

Benign

0.054

MetaRNN

Benign

0.047

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

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

1.4

L;.;.;.;.;.;.

PhyloP100

2.5

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.040

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

REVEL

Uncertain

0.32

Sift

Benign

0.13

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

Sift4G

Benign

0.78

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

Polyphen

0.34

B;.;.;P;P;.;P

Vest4

0.16

MVP

0.66

MPC

0.076

ClinPred

0.023

GERP RS

4.2

Varity_R

0.056

gMVP

0.39

Mutation Taster

=97/3

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over