rs199476092

Positions:

chr9-95467197-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_000264.5(PTCH1):c.2479A>G(p.Ser827Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000258 in 1,614,258 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00024 ( 3 hom. )

Consequence

PTCH1
NM_000264.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1U:1B:6O:1

Conservation

PhyloP100: 2.55

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:

LOC100507346 (HGNC:):

LOC100507346 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

PM1

In a topological_domain Extracellular (size 257) in uniprot entity PTC1_HUMAN there are 24 pathogenic changes around while only 5 benign (83%) in NM_000264.5

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PTCH1. . Gene score misZ 1.6774 (greater than the threshold 3.09). Trascript score misZ 3.1343 (greater than threshold 3.09). GenCC has associacion of gene with holoprosencephaly 7, nevoid basal cell carcinoma syndrome, holoprosencephaly.

BP4

Computational evidence support a benign effect (MetaRNN=0.013190687).

BP6

Variant 9-95467197-T-C is Benign according to our data. Variant chr9-95467197-T-C is described in ClinVar as [Benign]. Clinvar id is 8223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95467197-T-C is described in Lovd as [Likely_benign]. Variant chr9-95467197-T-C is described in Lovd as [Benign]. Variant chr9-95467197-T-C is described in Lovd as [Likely_pathogenic]. Variant chr9-95467197-T-C is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000459 (70/152368) while in subpopulation EAS AF= 0.0135 (70/5192). AF 95% confidence interval is 0.0109. There are 0 homozygotes in gnomad4. There are 49 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 70 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PTCH1	NM_000264.5 linkuse as main transcript	c.2479A>G	p.Ser827Gly	missense_variant	15/24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3 linkuse as main transcript	c.2476A>G	p.Ser826Gly	missense_variant	15/24	ENST00000437951.6	NP_001077072.1
LOC100507346	NR_038982.1 linkuse as main transcript	n.458T>C		non_coding_transcript_exon_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11 linkuse as main transcript	c.2479A>G	p.Ser827Gly	missense_variant	15/24	5	NM_000264.5	ENSP00000332353	A2	Q13635-1
PTCH1	ENST00000437951.6 linkuse as main transcript	c.2476A>G	p.Ser826Gly	missense_variant	15/24	5	NM_001083603.3	ENSP00000389744		Q13635-2

Frequencies

GnomAD3 genomes

AF:

0.000466

AC:

AN:

152250

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:

0.0136

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

GnomAD3 exomes

AF:

0.000986

AC:

248

AN:

251484

Hom.:

AF XY:

0.00100

AC XY:

136

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0127

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.000237

AC:

347

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000239

AC XY:

174

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00756

Gnomad4 SAS exome

AF:

0.000220

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000397

GnomAD4 genome

AF:

0.000459

AC:

AN:

152368

Hom.:

Cov.:

AF XY:

0.000658

AC XY:

AN XY:

74522

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0135

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000432

Hom.:

Bravo

AF:

0.000480

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000782

AC:

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Uncertain:1Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 13, 2020	This variant is associated with the following publications: (PMID: 31180159, 22995991, 24204797, 22313357, 22703879, 11941477, 24728327) -
Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 28, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 01, 2016	This alteration is classified as 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 specified

Benign:1Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 16, 2021	- -

Holoprosencephaly 7

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2002

- -

PTCH1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 21, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Gorlin syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.52

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

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.88

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

MetaRNN

Benign

0.013

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

MetaSVM

Benign

-0.73

MutationAssessor

Benign

0.33

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

MutationTaster

Benign

0.43

A;A;A;A;A;A;A

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.5

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

REVEL

Uncertain

0.41

Sift

Benign

0.43

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

Sift4G

Benign

0.46

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

Polyphen

0.0040

B;.;.;B;B;.;B

Vest4

0.46

MVP

0.95

MPC

0.51

ClinPred

0.033

GERP RS

4.3

Varity_R

0.22

gMVP

0.59

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

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