9-95508364-TGCCGCCGCCGCC-TGCCGCCGCCGCCGCC

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000264.5(PTCH1):c.-6_-4dupGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 1,163,256 control chromosomes in the GnomAD database, including 22,394 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4253 hom., cov: 22)

Exomes 𝑓: 0.21 ( 18141 hom. )

Consequence

PTCH1
NM_000264.5 5_prime_UTR

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 3.30

Publications

2 publications found

Variant links:

COSMIC-nc: COSV100108942

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 Gene-Disease associations (from GenCC):

basal cell nevus syndrome 1
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
holoprosencephaly 7
Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
nevoid basal cell carcinoma syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
holoprosencephaly
Inheritance: AD Classification: LIMITED Submitted by: Illumina

PTCH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 9-95508364-T-TGCC is Benign according to our data. Variant chr9-95508364-T-TGCC is described in ClinVar as Benign. ClinVar VariationId is 132684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5 link	c.-6_-4dupGGC		5_prime_UTR_variant	Exon 1 of 24	ENST00000331920.11	NP_000255.2	Q13635-1
PTCH1	NM_001083603.3 link	c.199-1768_199-1766dupGGC		intron_variant	Intron 1 of 23	ENST00000437951.6	NP_001077072.1	Q13635-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11 link	c.-6_-4dupGGC		5_prime_UTR_variant	Exon 1 of 24	5	NM_000264.5	ENSP00000332353.6		Q13635-1
PTCH1	ENST00000437951.6 link	c.199-1768_199-1766dupGGC		intron_variant	Intron 1 of 23	5	NM_001083603.3	ENSP00000389744.2		Q13635-2

Frequencies

GnomAD3 genomes

AF:

0.235

AC:

34642

AN:

147642

Hom.:

4237

Cov.:

show subpopulations

Gnomad AFR

AF:

0.280

Gnomad AMI

AF:

0.201

Gnomad AMR

AF:

0.147

Gnomad ASJ

AF:

0.292

Gnomad EAS

AF:

0.228

Gnomad SAS

AF:

0.165

Gnomad FIN

AF:

0.258

Gnomad MID

AF:

0.206

Gnomad NFE

AF:

0.227

Gnomad OTH

AF:

0.219

GnomAD2 exomes

AF:

0.119

AC:

177

AN:

1492

AF XY:

0.117

show subpopulations

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0500

Gnomad FIN exome

AF:

0.0313

Gnomad NFE exome

AF:

0.129

Gnomad OTH exome

AF:

0.211

GnomAD4 exome

AF:

0.205

AC:

208647

AN:

1015512

Hom.:

18141

Cov.:

AF XY:

0.205

AC XY:

98564

AN XY:

480486

show subpopulations

African (AFR)

AF:

0.261

AC:

5255

AN:

20156

American (AMR)

AF:

0.0920

AC:

609

AN:

6616

Ashkenazi Jewish (ASJ)

AF:

0.234

AC:

2589

AN:

11074

East Asian (EAS)

AF:

0.151

AC:

3158

AN:

20856

South Asian (SAS)

AF:

0.166

AC:

3161

AN:

19036

European-Finnish (FIN)

AF:

0.176

AC:

3201

AN:

18146

Middle Eastern (MID)

AF:

0.188

AC:

481

AN:

2562

European-Non Finnish (NFE)

AF:

0.208

AC:

182555

AN:

878254

Other (OTH)

AF:

0.197

AC:

7638

AN:

38812

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

8472

16944

25417

33889

42361

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8018

16036

24054

32072

40090

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.235

AC:

34683

AN:

147744

Hom.:

4253

Cov.:

AF XY:

0.233

AC XY:

16780

AN XY:

71992

show subpopulations

African (AFR)

AF:

0.280

AC:

11412

AN:

40706

American (AMR)

AF:

0.146

AC:

2190

AN:

14950

Ashkenazi Jewish (ASJ)

AF:

0.292

AC:

993

AN:

3396

East Asian (EAS)

AF:

0.227

AC:

1122

AN:

4940

South Asian (SAS)

AF:

0.166

AC:

789

AN:

4750

European-Finnish (FIN)

AF:

0.258

AC:

2416

AN:

9382

Middle Eastern (MID)

AF:

0.210

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.227

AC:

15058

AN:

66394

Other (OTH)

AF:

0.226

AC:

463

AN:

2046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1255

2509

3764

5018

6273

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

354

708

1062

1416

1770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0927

Hom.:

138

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 24, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:flagged submission

Collection Method:clinical testing

- -

Aug 30, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: c.-6_-4dupGGC affects mildly conserved nucleotides, resulting in duplication of 3 nucleotides in the 5UTR region. This variant was found in 1014/5008 control chromosomes of 1000Gs project at a frequency of 0.2024, which greatly exceeds the maximal expected frequency of a pathogenic allele (0.000017). The variant has been reported as Benign by several reputable databases/clinical laboratories without evidence to independently evaluate. Taking together, based on the prevalence in the general population, the variant was classified as Benign. -

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:3

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 25, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 24, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PTCH1-related disorder

Benign:1

May 08, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Jul 06, 2020

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over