rs2066829

Positions:

chr9-95467107-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000264.5(PTCH1):c.2560+9G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 1,613,226 control chromosomes in the GnomAD database, including 111,251 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.43 ( 15606 hom., cov: 32)

Exomes 𝑓: 0.36 ( 95645 hom. )

Consequence

PTCH1
NM_000264.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.352

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BP6

Variant 9-95467107-C-G is Benign according to our data. Variant chr9-95467107-C-G is described in ClinVar as [Benign]. Clinvar id is 255677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95467107-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.637 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH1	NM_000264.5 linkuse as main transcript	c.2560+9G>C		intron_variant		ENST00000331920.11	NP_000255.2	Q13635-1
PTCH1	NM_001083603.3 linkuse as main transcript	c.2557+9G>C		intron_variant		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.2560+9G>C		intron_variant		5	NM_000264.5	ENSP00000332353.6		Q13635-1
PTCH1	ENST00000437951.6 linkuse as main transcript	c.2557+9G>C		intron_variant		5	NM_001083603.3	ENSP00000389744.2		Q13635-2

Frequencies

GnomAD3 genomes

AF:

0.429

AC:

65163

AN:

151852

Hom.:

15553

Cov.:

show subpopulations

Gnomad AFR

AF:

0.643

Gnomad AMI

AF:

0.419

Gnomad AMR

AF:

0.259

Gnomad ASJ

AF:

0.413

Gnomad EAS

AF:

0.343

Gnomad SAS

AF:

0.253

Gnomad FIN

AF:

0.377

Gnomad MID

AF:

0.328

Gnomad NFE

AF:

0.367

Gnomad OTH

AF:

0.386

GnomAD3 exomes

AF:

0.347

AC:

87041

AN:

250766

Hom.:

16607

AF XY:

0.344

AC XY:

46595

AN XY:

135610

show subpopulations

Gnomad AFR exome

AF:

0.652

Gnomad AMR exome

AF:

0.184

Gnomad ASJ exome

AF:

0.405

Gnomad EAS exome

AF:

0.349

Gnomad SAS exome

AF:

0.261

Gnomad FIN exome

AF:

0.373

Gnomad NFE exome

AF:

0.366

Gnomad OTH exome

AF:

0.347

GnomAD4 exome

AF:

0.356

AC:

520243

AN:

1461256

Hom.:

95645

Cov.:

AF XY:

0.354

AC XY:

257217

AN XY:

726946

show subpopulations

Gnomad4 AFR exome

AF:

0.654

Gnomad4 AMR exome

AF:

0.192

Gnomad4 ASJ exome

AF:

0.416

Gnomad4 EAS exome

AF:

0.321

Gnomad4 SAS exome

AF:

0.265

Gnomad4 FIN exome

AF:

0.372

Gnomad4 NFE exome

AF:

0.360

Gnomad4 OTH exome

AF:

0.360

GnomAD4 genome

AF:

0.430

AC:

65279

AN:

151970

Hom.:

15606

Cov.:

AF XY:

0.422

AC XY:

31382

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.644

Gnomad4 AMR

AF:

0.258

Gnomad4 ASJ

AF:

0.413

Gnomad4 EAS

AF:

0.342

Gnomad4 SAS

AF:

0.254

Gnomad4 FIN

AF:

0.377

Gnomad4 NFE

AF:

0.367

Gnomad4 OTH

AF:

0.391

Alfa

AF:

0.389

Hom.:

3886

Bravo

AF:

0.431

Asia WGS

AF:

0.328

AC:

1140

AN:

3478

EpiCase

AF:

0.358

EpiControl

AF:

0.363

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Gorlin syndrome

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 24, 2016	Variant summary: The PTCH1 c.2560+9G>C variant involves the alteration of a non-conserved intronic nucleotide. 5/5 splice prediction tools predict no significant impact on normal splicing, however these predictions are yet to be confirmed by functional studies. This variant was found in 43313/120886 control chromosomes (8491 homozygotes) at an overall frequency of 0.3582962, which significantly exceeds the estimated maximal allele frequency of a pathogenic PTCH1 variant (0.0000171), suggesting this variant is a benign polymorphism. Taken together, based on the prevalence in the general population this variant is classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Holoprosencephaly 7

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

2.1

DANN

Benign

0.20

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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