9-95508364-TGCCGCCGCCGCC-TGCC

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000264.5(PTCH1):c.-12_-4delGGCGGCGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000637 in 1,163,798 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 22)

Exomes 𝑓: 0.00065 ( 1 hom. )

Consequence

PTCH1
NM_000264.5 5_prime_UTR

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.30

Publications

2 publications found

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 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-TGCCGCCGCC-T is Benign according to our data. Variant chr9-95508364-TGCCGCCGCC-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 215454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000649 (659/1015956) while in subpopulation NFE AF = 0.000628 (552/878566). AF 95% confidence interval is 0.000585. There are 1 homozygotes in GnomAdExome4. There are 308 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.

BS2

High AC in GnomAd4 at 82 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5 link	c.-12_-4delGGCGGCGGC		5_prime_UTR_variant	Exon 1 of 24	ENST00000331920.11	NP_000255.2	Q13635-1
PTCH1	NM_001083603.3 link	c.199-1774_199-1766delGGCGGCGGC		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.-12_-4delGGCGGCGGC		5_prime_UTR_variant	Exon 1 of 24	5	NM_000264.5	ENSP00000332353.6		Q13635-1
PTCH1	ENST00000437951.6 link	c.199-1774_199-1766delGGCGGCGGC		intron_variant	Intron 1 of 23	5	NM_001083603.3	ENSP00000389744.2		Q13635-2

Frequencies

GnomAD3 genomes

AF:

0.000555

AC:

AN:

147736

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000271

Gnomad AMI

AF:

0.00112

Gnomad AMR

AF:

0.000603

Gnomad ASJ

AF:

0.00235

Gnomad EAS

AF:

0.000604

Gnomad SAS

AF:

0.000421

Gnomad FIN

AF:

0.00128

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000542

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000670

AC:

AN:

1492

AF XY:

0.00116

show subpopulations

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000790

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000649

AC:

659

AN:

1015956

Hom.:

AF XY:

0.000641

AC XY:

308

AN XY:

480704

show subpopulations

African (AFR)

AF:

0.000446

AC:

AN:

20162

American (AMR)

AF:

0.000604

AC:

AN:

6622

Ashkenazi Jewish (ASJ)

AF:

0.00270

AC:

AN:

11094

East Asian (EAS)

AF:

0.000431

AC:

AN:

20892

South Asian (SAS)

AF:

0.000578

AC:

AN:

19040

European-Finnish (FIN)

AF:

0.000825

AC:

AN:

18176

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2568

European-Non Finnish (NFE)

AF:

0.000628

AC:

552

AN:

878566

Other (OTH)

AF:

0.000747

AC:

AN:

38836

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

120

150

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.000555

AC:

AN:

147842

Hom.:

Cov.:

AF XY:

0.000639

AC XY:

AN XY:

72038

show subpopulations

African (AFR)

AF:

0.000270

AC:

AN:

40744

American (AMR)

AF:

0.000602

AC:

AN:

14952

Ashkenazi Jewish (ASJ)

AF:

0.00235

AC:

AN:

3398

East Asian (EAS)

AF:

0.000606

AC:

AN:

4948

South Asian (SAS)

AF:

0.000421

AC:

AN:

4752

European-Finnish (FIN)

AF:

0.00128

AC:

AN:

9392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000542

AC:

AN:

66430

Other (OTH)

AF:

0.00

AC:

AN:

2046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

138

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 09, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 29, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Gorlin syndrome

Benign:1

Aug 26, 2015

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Apr 06, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.3

Mutation Taster

=271/29

polymorphism

(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