Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000264.5(PTCH1):c.2799G>A(p.Ala933Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000725 in 1,614,168 control chromosomes in the GnomAD database, including 5 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. A933A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0035 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00044 ( 3 hom. )

Consequence

PTCH1
NM_000264.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -1.21

Publications

3 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 9-95459688-C-T is Benign according to our data. Variant chr9-95459688-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 215457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.21 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00349 (531/152294) while in subpopulation AFR AF = 0.0119 (494/41562). AF 95% confidence interval is 0.011. There are 2 homozygotes in GnomAd4. There are 241 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 531 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000264.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PTCH1	NM_000264.5	MANE Select	c.2799G>A	p.Ala933Ala	synonymous	Exon 17 of 24	NP_000255.2
PTCH1	NM_001083603.3	MANE Plus Clinical	c.2796G>A	p.Ala932Ala	synonymous	Exon 17 of 24	NP_001077072.1
PTCH1	NM_001354918.2		c.2643G>A	p.Ala881Ala	synonymous	Exon 16 of 23	NP_001341847.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PTCH1	ENST00000331920.11	TSL:5 MANE Select	c.2799G>A	p.Ala933Ala	synonymous	Exon 17 of 24	ENSP00000332353.6
PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.2796G>A	p.Ala932Ala	synonymous	Exon 17 of 24	ENSP00000389744.2
PTCH1	ENST00000429896.6	TSL:1	c.2346G>A	p.Ala782Ala	synonymous	Exon 17 of 24	ENSP00000414823.2

Frequencies

GnomAD3 genomes

AF:

0.00347

AC:

528

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00104

AC:

261

AN:

251478

AF XY:

0.000750

show subpopulations

Gnomad AFR exome

AF:

0.0129

Gnomad AMR exome

AF:

0.000578

Gnomad ASJ exome

AF:

0.00188

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000615

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000438

AC:

640

AN:

1461874

Hom.:

Cov.:

AF XY:

0.000348

AC XY:

253

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.0123

AC:

411

AN:

33480

American (AMR)

AF:

0.000559

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00210

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000521

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000387

AC:

AN:

1112010

Other (OTH)

AF:

0.00166

AC:

100

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

144

192

240

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00349

AC:

531

AN:

152294

Hom.:

Cov.:

AF XY:

0.00324

AC XY:

241

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0119

AC:

494

AN:

41562

American (AMR)

AF:

0.00137

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3466

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68026

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00178

Hom.:

Bravo

AF:

0.00411

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Gorlin syndrome (3)

Hereditary cancer-predisposing syndrome (2)

not provided (2)

not specified (2)

Holoprosencephaly 7 (1)

Holoprosencephaly 7;C2751544:Basal cell carcinoma, susceptibility to, 1;CN376810:Basal cell nevus syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.74

(source)

DANN

Benign

0.62

PhyloP100

-1.2

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over