rs73527759

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001083603.3(PTCH1):c.163G>C(p.Asp55His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00495 in 1,611,754 control chromosomes in the GnomAD database, including 274 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 136 hom., cov: 31)

Exomes 𝑓: 0.0029 ( 138 hom. )

Consequence

PTCH1
NM_001083603.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: 1.92

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 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 3.2707 (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=0.0015723407).

BP6

Variant 9-95516658-C-G is Benign according to our data. Variant chr9-95516658-C-G is described in ClinVar as [Benign]. Clinvar id is 41769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95516658-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0801 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PTCH1	NM_001083603.3 linkuse as main transcript	c.163G>C	p.Asp55His	missense_variant	1/24	ENST00000437951.6	NP_001077072.1
PTCH1	NM_001083602.3 linkuse as main transcript	c.-187G>C		5_prime_UTR_variant	1/24		NP_001077071.1
PTCH1	NM_001354919.2 linkuse as main transcript	c.-187G>C		5_prime_UTR_variant	1/5		NP_001341848.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000437951.6 linkuse as main transcript	c.163G>C	p.Asp55His	missense_variant	1/24	5	NM_001083603.3	ENSP00000389744		Q13635-2

Frequencies

GnomAD3 genomes

AF:

0.0243

AC:

3687

AN:

151960

Hom.:

133

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0823

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0125

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000471

Gnomad OTH

AF:

0.0191

GnomAD3 exomes

AF:

0.00664

AC:

1632

AN:

245646

Hom.:

AF XY:

0.00515

AC XY:

689

AN XY:

133688

show subpopulations

Gnomad AFR exome

AF:

0.0856

Gnomad AMR exome

AF:

0.00586

Gnomad ASJ exome

AF:

0.00550

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000132

Gnomad FIN exome

AF:

0.0000931

Gnomad NFE exome

AF:

0.000413

Gnomad OTH exome

AF:

0.00420

GnomAD4 exome

AF:

0.00294

AC:

4287

AN:

1459676

Hom.:

138

Cov.:

AF XY:

0.00263

AC XY:

1908

AN XY:

726138

show subpopulations

Gnomad4 AFR exome

AF:

0.0893

Gnomad4 AMR exome

AF:

0.00666

Gnomad4 ASJ exome

AF:

0.00563

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000815

Gnomad4 FIN exome

AF:

0.0000568

Gnomad4 NFE exome

AF:

0.000365

Gnomad4 OTH exome

AF:

0.00707

GnomAD4 genome

AF:

0.0243

AC:

3699

AN:

152078

Hom.:

136

Cov.:

AF XY:

0.0237

AC XY:

1762

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0824

Gnomad4 AMR

AF:

0.0124

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.0000945

Gnomad4 NFE

AF:

0.000471

Gnomad4 OTH

AF:

0.0189

Alfa

AF:

0.00802

Hom.:

Bravo

AF:

0.0282

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0787

AC:

297

ESP6500EA

AF:

0.000610

AC:

ExAC

AF:

0.00740

AC:

894

Asia WGS

AF:

0.00693

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000594

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 14, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -

not specified

Benign:1Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.65

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.29

MetaRNN

Benign

0.0016

MetaSVM

Benign

-0.80

MutationTaster

Benign

1.0

D;D;D;N

PROVEAN

Benign

-0.19

REVEL

Benign

0.14

Sift

Benign

0.072

Sift4G

Benign

0.18

Polyphen

0.042

Vest4

0.30

MVP

0.29

ClinPred

0.0057

GERP RS

3.1

Splicing

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