9-95447312-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM2PM5PP2BP6

The NM_000264.5(PTCH1):c.3944C>A(p.Pro1315His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,612,906 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P1315R) has been classified as Likely benign.

Frequency

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

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PTCH1
NM_000264.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.54

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-95447312-G-A is described in Lovd as [Pathogenic].

PP2

Missense variant where missense usually causes diseases, PTCH1

BP6

Variant 9-95447312-G-T is Benign according to our data. Variant chr9-95447312-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 409178.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH1	NM_000264.5 linkuse as main transcript	c.3944C>A	p.Pro1315His	missense_variant	23/24	ENST00000331920.11
PTCH1	NM_001083603.3 linkuse as main transcript	c.3941C>A	p.Pro1314His	missense_variant	23/24	ENST00000437951.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11 linkuse as main transcript	c.3944C>A	p.Pro1315His	missense_variant	23/24	5	NM_000264.5	A2	Q13635-1
PTCH1	ENST00000437951.6 linkuse as main transcript	c.3941C>A	p.Pro1314His	missense_variant	23/24	5	NM_001083603.3		Q13635-2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151992

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000406

AC:

AN:

246178

Hom.:

AF XY:

0.00000744

AC XY:

AN XY:

134464

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000904

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460914

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726768

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151992

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74216

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000831

AC:

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 01, 2021

The c.3944C>A (p.P1315H) alteration is located in exon 23 (coding exon 23) of the PTCH1 gene. This alteration results from a C to A substitution at nucleotide position 3944, causing the proline (P) at amino acid position 1315 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Gorlin syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 18, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.37

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

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.91

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

M_CAP

Uncertain

0.26

MetaRNN

Uncertain

0.46

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

MetaSVM

Uncertain

0.54

MutationAssessor

Uncertain

2.3

M;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.2

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

REVEL

Uncertain

0.47

Sift

Uncertain

0.011

D;D;D;D;D;D;D

Sift4G

Benign

0.18

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

Polyphen

1.0

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

Vest4

0.64

MutPred

0.11

Loss of glycosylation at P1315 (P = 0.0204);.;.;.;.;.;.;

MVP

0.38

MPC

0.44

ClinPred

0.91

GERP RS

4.8

Varity_R

0.28

gMVP

0.53

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over