NM_000264.5:c.1238A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_000264.5(PTCH1):c.1238A>G(p.Gln413Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q413H) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

PTCH1
NM_000264.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.683

Publications

1 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13024062).

BP6

Variant 9-95478164-T-C is Benign according to our data. Variant chr9-95478164-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 574054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95478164-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 574054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95478164-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 574054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95478164-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 574054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95478164-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 574054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95478164-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 574054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95478164-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 574054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95478164-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 574054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95478164-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 574054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95478164-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 574054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95478164-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 574054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95478164-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 574054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95478164-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 574054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95478164-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 574054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95478164-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 574054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5 link	c.1238A>G	p.Gln413Arg	missense_variant	Exon 9 of 24	ENST00000331920.11	NP_000255.2	Q13635-1
PTCH1	NM_001083603.3 link	c.1235A>G	p.Gln412Arg	missense_variant	Exon 9 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.1238A>G	p.Gln413Arg	missense_variant	Exon 9 of 24	5	NM_000264.5	ENSP00000332353.6		Q13635-1
PTCH1	ENST00000437951.6 link	c.1235A>G	p.Gln412Arg	missense_variant	Exon 9 of 24	5	NM_001083603.3	ENSP00000389744.2		Q13635-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152196

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:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251488

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112012

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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.:

Bravo

AF:

0.0000227

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Gorlin syndrome

Benign:1

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

May 19, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.39

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

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.81

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

M_CAP

Benign

0.056

MetaRNN

Benign

0.13

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

MetaSVM

Benign

-0.47

MutationAssessor

Benign

0.34

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

PhyloP100

0.68

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.1

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

REVEL

Benign

0.14

Sift

Benign

0.50

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

Sift4G

Benign

0.50

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

Polyphen

0.0040

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

Vest4

0.23

MutPred

0.37

Loss of loop (P = 0.0235);.;.;.;.;.;.;.;

MVP

0.60

MPC

0.59

ClinPred

0.072

GERP RS

0.31

Varity_R

0.14

gMVP

0.14

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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