chr9-95478096-C-T

Position:

chr9-95478096-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_000264.5(PTCH1):c.1306G>A(p.Asp436Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000929 in 1,614,178 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. D436D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00084 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00094 ( 1 hom. )

Consequence

PTCH1
NM_000264.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:9O:1

Conservation

PhyloP100: 3.83

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:

PTCH1 (HGNC:):

PTCH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

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=0.054343313).

BP6

Variant 9-95478096-C-T is Benign according to our data. Variant chr9-95478096-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 135110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95478096-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000841 (128/152288) while in subpopulation AMR AF= 0.00216 (33/15304). AF 95% confidence interval is 0.00158. There are 0 homozygotes in gnomad4. There are 59 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 128 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH1	NM_000264.5 linkuse as main transcript	c.1306G>A	p.Asp436Asn	missense_variant	9/24	ENST00000331920.11	NP_000255.2	Q13635-1
PTCH1	NM_001083603.3 linkuse as main transcript	c.1303G>A	p.Asp435Asn	missense_variant	9/24	ENST00000437951.6	NP_001077072.1	Q13635-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11 linkuse as main transcript	c.1306G>A	p.Asp436Asn	missense_variant	9/24	5	NM_000264.5	ENSP00000332353.6		Q13635-1
PTCH1	ENST00000437951.6 linkuse as main transcript	c.1303G>A	p.Asp435Asn	missense_variant	9/24	5	NM_001083603.3	ENSP00000389744.2		Q13635-2

Frequencies

GnomAD3 genomes

AF:

0.000841

AC:

128

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000740

AC:

186

AN:

251476

Hom.:

AF XY:

0.000736

AC XY:

100

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00119

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000554

Gnomad NFE exome

AF:

0.00105

Gnomad OTH exome

AF:

0.000977

GnomAD4 exome

AF:

0.000938

AC:

1371

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000902

AC XY:

656

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.00143

Gnomad4 ASJ exome

AF:

0.000306

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.000580

Gnomad4 NFE exome

AF:

0.00106

Gnomad4 OTH exome

AF:

0.00111

GnomAD4 genome

AF:

0.000841

AC:

128

AN:

152288

Hom.:

Cov.:

AF XY:

0.000792

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00101

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000733

Hom.:

Bravo

AF:

0.000831

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000725

AC:

EpiCase

AF:

0.000763

EpiControl

AF:

0.000771

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Gorlin syndrome

Benign:3

Likely benign, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 28, 2018	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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Sep 08, 2020	- -

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	Apr 01, 2021	- -

Hirschsprung disease, susceptibility to, 1

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Department of Genetics, Reproduction and Fetal Medicine., Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville.

Apr 01, 2015

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 12, 2019

This variant is associated with the following publications: (PMID: 16231297, 16405370, 23334667, 26893459, 26559152, 28717660, 25527561, 24728327) -

Anophthalmia-microphthalmia syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing;research

Paul Sabatier University EA-4555, Paul Sabatier University

Jan 01, 2013

rare variant, functional studies demonstrating absence of deleterious effect on protein. -

Holoprosencephaly 7

Benign:1

Likely benign, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

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

Eigen

Benign

0.0036

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

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

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.054

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

MetaSVM

Uncertain

0.50

MutationAssessor

Benign

1.1

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

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-1.3

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

REVEL

Uncertain

0.32

Sift

Benign

0.15

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

Sift4G

Benign

0.46

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

Polyphen

0.12

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

Vest4

0.42

MVP

0.51

MPC

0.54

ClinPred

0.024

GERP RS

5.6

Varity_R

0.23

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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