rs138911275

Positions:

chr9-95458026-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PM1PP2BS1BS2

The NM_000264.5(PTCH1):c.3155C>T(p.Thr1052Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,613,990 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00061 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 2 hom. )

Consequence

PTCH1
NM_000264.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:13O:1

Conservation

PhyloP100: 7.64

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 Likely_benign. Variant got -5 ACMG points.

PM1

In a helix (size 23) in uniprot entity PTC1_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) 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.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00127 (1858/1461810) while in subpopulation NFE AF= 0.00157 (1750/1112002). AF 95% confidence interval is 0.00151. There are 2 homozygotes in gnomad4_exome. There are 870 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 93 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH1	NM_000264.5 linkuse as main transcript	c.3155C>T	p.Thr1052Met	missense_variant	18/24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3 linkuse as main transcript	c.3152C>T	p.Thr1051Met	missense_variant	18/24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11 linkuse as main transcript	c.3155C>T	p.Thr1052Met	missense_variant	18/24	5	NM_000264.5	ENSP00000332353	A2	Q13635-1
PTCH1	ENST00000437951.6 linkuse as main transcript	c.3152C>T	p.Thr1051Met	missense_variant	18/24	5	NM_001083603.3	ENSP00000389744		Q13635-2

Frequencies

GnomAD3 genomes

AF:

0.000611

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

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:

0.00107

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000649

AC:

163

AN:

251056

Hom.:

AF XY:

0.000648

AC XY:

AN XY:

135778

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.000636

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00119

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00127

AC:

1858

AN:

1461810

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

870

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000626

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00157

Gnomad4 OTH exome

AF:

0.00116

GnomAD4 genome

AF:

0.000611

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000632

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00107

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00110

Hom.:

Bravo

AF:

0.000578

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000618

AC:

EpiCase

AF:

0.00131

EpiControl

AF:

0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:13Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:8

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	PTCH1: BS1 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 26893459, 26353884, 27498913, 22885699, 11941477, 24728327, 26875496, 22703879, 21188540, 24055113, 25637381, 22820256, 23718828, 17001668, 20635334, 24686850, 24211491, 26489027, 26986070, 27153395, 27930734, 29575684, 33209614) -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 04, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Holoprosencephaly 7

Pathogenic:1Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2006	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Uncertain:1Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 26, 2018	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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 04, 2020	- -

PTCH1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 17, 2020

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

Holoprosencephaly sequence

Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

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

0.13

BayesDel_addAF

Uncertain

0.082

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

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

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

T;.;D;T;.;.;T

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.54

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

MetaSVM

Uncertain

0.36

MutationAssessor

Uncertain

2.6

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

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-2.2

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

REVEL

Pathogenic

0.69

Sift

Uncertain

0.021

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

Sift4G

Benign

0.092

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

Polyphen

0.95

P;.;.;P;P;.;D

Vest4

0.93

MVP

0.83

MPC

1.5

ClinPred

0.18

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.60

gMVP

0.83

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