dbSNP rs2066835: PTCH1:p.Leu1047Leu (chr9-95458040-A-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000264.5(PTCH1):c.3141T>G(p.Leu1047Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,614,126 control chromosomes in the GnomAD database, including 872 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1047L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.038 ( 293 hom., cov: 33)

Exomes 𝑓: 0.0096 ( 579 hom. )

Consequence

PTCH1
NM_000264.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.132

Publications

9 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=-0.58).

BP6

Variant 9-95458040-A-C is Benign according to our data. Variant chr9-95458040-A-C is described in ClinVar as Benign. ClinVar VariationId is 255681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.132 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

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.3141T>G	p.Leu1047Leu	synonymous	Exon 18 of 24	NP_000255.2
PTCH1	NM_001083603.3	MANE Plus Clinical	c.3138T>G	p.Leu1046Leu	synonymous	Exon 18 of 24	NP_001077072.1
PTCH1	NM_001354918.2		c.2985T>G	p.Leu995Leu	synonymous	Exon 17 of 23	NP_001341847.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PTCH1	ENST00000331920.11	TSL:5 MANE Select	c.3141T>G	p.Leu1047Leu	synonymous	Exon 18 of 24	ENSP00000332353.6
PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.3138T>G	p.Leu1046Leu	synonymous	Exon 18 of 24	ENSP00000389744.2
PTCH1	ENST00000429896.6	TSL:1	c.2688T>G	p.Leu896Leu	synonymous	Exon 18 of 24	ENSP00000414823.2

Frequencies

GnomAD3 genomes

AF:

0.0376

AC:

5716

AN:

152164

Hom.:

293

Cov.:

show subpopulations

Gnomad AFR

AF:

0.112

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0124

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0971

Gnomad SAS

AF:

0.0484

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00141

Gnomad OTH

AF:

0.0229

GnomAD2 exomes

AF:

0.0215

AC:

5393

AN:

251214

AF XY:

0.0205

show subpopulations

Gnomad AFR exome

AF:

0.113

Gnomad AMR exome

AF:

0.00497

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.101

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00123

Gnomad OTH exome

AF:

0.00929

GnomAD4 exome

AF:

0.00956

AC:

13973

AN:

1461844

Hom.:

579

Cov.:

AF XY:

0.0101

AC XY:

7345

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.117

AC:

3928

AN:

33480

American (AMR)

AF:

0.00584

AC:

261

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000574

AC:

AN:

26136

East Asian (EAS)

AF:

0.0944

AC:

3748

AN:

39700

South Asian (SAS)

AF:

0.0427

AC:

3683

AN:

86256

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53374

Middle Eastern (MID)

AF:

0.00954

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00117

AC:

1305

AN:

1112012

Other (OTH)

AF:

0.0161

AC:

975

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

906

1812

2717

3623

4529

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

252

504

756

1008

1260

<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:

0.0376

AC:

5728

AN:

152282

Hom.:

293

Cov.:

AF XY:

0.0380

AC XY:

2827

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.112

AC:

4652

AN:

41546

American (AMR)

AF:

0.0123

AC:

188

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.0974

AC:

504

AN:

5176

South Asian (SAS)

AF:

0.0486

AC:

235

AN:

4832

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00141

AC:

AN:

68018

Other (OTH)

AF:

0.0227

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

266

532

797

1063

1329

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<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:

0.0237

Hom.:

183

Bravo

AF:

0.0415

Asia WGS

AF:

0.0610

AC:

210

AN:

3478

EpiCase

AF:

0.00180

EpiControl

AF:

0.00119

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Gorlin syndrome (3)

not provided (3)

not specified (3)

Hereditary cancer-predisposing syndrome (1)

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

-0.58

CADD

Benign

5.9

(source)

DANN

Benign

0.67

PhyloP100

0.13

Mutation Taster

=79/21

polymorphism (auto)

(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

Computational scores

Splicing

Publications

Other links and lift over