dbSNP rs2227970: PTCH1:p.Ser733Ser (chr9-95468802-T-C) – ACMG Classification: Benign (-21 pts)

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.2199A>G(p.Ser733Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 1,614,154 control chromosomes in the GnomAD database, including 224 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. S733S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.012 ( 28 hom., cov: 32)

Exomes 𝑓: 0.016 ( 196 hom. )

Consequence

PTCH1
NM_000264.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: -1.34

Publications

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

PTCH1 links:

LOC100507346 (HGNC:):

LOC100507346 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=-0.62).

BP6

Variant 9-95468802-T-C is Benign according to our data. Variant chr9-95468802-T-C is described in ClinVar as Benign. ClinVar VariationId is 132699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.34 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0118 (1797/152274) while in subpopulation EAS AF = 0.0307 (159/5182). AF 95% confidence interval is 0.0268. There are 28 homozygotes in GnomAd4. There are 922 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1797 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	UniProt
PTCH1	NM_000264.5	MANE Select	c.2199A>G	p.Ser733Ser	synonymous	Exon 14 of 24	NP_000255.2	Q13635-1
PTCH1	NM_001083603.3	MANE Plus Clinical	c.2196A>G	p.Ser732Ser	synonymous	Exon 14 of 24	NP_001077072.1	Q13635-2
PTCH1	NM_001354918.2		c.2043A>G	p.Ser681Ser	synonymous	Exon 13 of 23	NP_001341847.1	A0A1W5YLI7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PTCH1	ENST00000331920.11	TSL:5 MANE Select	c.2199A>G	p.Ser733Ser	synonymous	Exon 14 of 24	ENSP00000332353.6	Q13635-1
PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.2196A>G	p.Ser732Ser	synonymous	Exon 14 of 24	ENSP00000389744.2	Q13635-2
PTCH1	ENST00000429896.6	TSL:1	c.1746A>G	p.Ser582Ser	synonymous	Exon 14 of 24	ENSP00000414823.2	Q13635-4

Frequencies

GnomAD3 genomes

AF:

0.0117

AC:

1777

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00292

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00969

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.0308

Gnomad SAS

AF:

0.0238

Gnomad FIN

AF:

0.0120

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0152

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.0145

AC:

3639

AN:

251494

AF XY:

0.0154

show subpopulations

Gnomad AFR exome

AF:

0.00197

Gnomad AMR exome

AF:

0.00685

Gnomad ASJ exome

AF:

0.0141

Gnomad EAS exome

AF:

0.0290

Gnomad FIN exome

AF:

0.0119

Gnomad NFE exome

AF:

0.0147

Gnomad OTH exome

AF:

0.0171

GnomAD4 exome

AF:

0.0157

AC:

22997

AN:

1461880

Hom.:

196

Cov.:

AF XY:

0.0158

AC XY:

11525

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00185

AC:

AN:

33480

American (AMR)

AF:

0.00698

AC:

312

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0135

AC:

352

AN:

26134

East Asian (EAS)

AF:

0.0252

AC:

999

AN:

39700

South Asian (SAS)

AF:

0.0190

AC:

1642

AN:

86258

European-Finnish (FIN)

AF:

0.0119

AC:

636

AN:

53420

Middle Eastern (MID)

AF:

0.0146

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0161

AC:

17918

AN:

1112000

Other (OTH)

AF:

0.0164

AC:

992

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

1480

2960

4441

5921

7401

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

690

1380

2070

2760

3450

<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:

0.0118

AC:

1797

AN:

152274

Hom.:

Cov.:

AF XY:

0.0124

AC XY:

922

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00291

AC:

121

AN:

41552

American (AMR)

AF:

0.00967

AC:

148

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

AN:

3470

East Asian (EAS)

AF:

0.0307

AC:

159

AN:

5182

South Asian (SAS)

AF:

0.0238

AC:

115

AN:

4826

European-Finnish (FIN)

AF:

0.0120

AC:

127

AN:

10610

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0152

AC:

1035

AN:

68012

Other (OTH)

AF:

0.0208

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

188

283

377

471

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0127

Hom.:

Bravo

AF:

0.0106

Asia WGS

AF:

0.0550

AC:

190

AN:

3478

EpiCase

AF:

0.0156

EpiControl

AF:

0.0156

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (4)

Gorlin syndrome (3)

Hereditary cancer-predisposing syndrome (3)

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

-0.62

CADD

Benign

0.33

(source)

DANN

Benign

0.66

PhyloP100

-1.3

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

Computational scores

Splicing

Publications

Other links and lift over