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.3567C>T(p.Gly1189Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,552,730 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0061 ( 7 hom., cov: 33)

Exomes 𝑓: 0.00060 ( 7 hom. )

Consequence

PTCH1
NM_000264.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.295

Publications

4 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=-0.7).

BP6

Variant 9-95449306-G-A is Benign according to our data. Variant chr9-95449306-G-A is described in ClinVar as Benign. ClinVar VariationId is 220553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.295 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00606 (923/152384) while in subpopulation AFR AF = 0.0213 (887/41592). AF 95% confidence interval is 0.0202. There are 7 homozygotes in GnomAd4. There are 427 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 923 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.3567C>T	p.Gly1189Gly	synonymous	Exon 22 of 24	NP_000255.2
PTCH1	NM_001083603.3	MANE Plus Clinical	c.3564C>T	p.Gly1188Gly	synonymous	Exon 22 of 24	NP_001077072.1
PTCH1	NM_001354918.2		c.3411C>T	p.Gly1137Gly	synonymous	Exon 21 of 23	NP_001341847.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PTCH1	ENST00000331920.11	TSL:5 MANE Select	c.3567C>T	p.Gly1189Gly	synonymous	Exon 22 of 24	ENSP00000332353.6
PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.3564C>T	p.Gly1188Gly	synonymous	Exon 22 of 24	ENSP00000389744.2
PTCH1	ENST00000429896.6	TSL:1	c.3114C>T	p.Gly1038Gly	synonymous	Exon 22 of 24	ENSP00000414823.2

Frequencies

GnomAD3 genomes

AF:

0.00606

AC:

922

AN:

152266

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0214

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00149

AC:

234

AN:

157404

AF XY:

0.00109

show subpopulations

Gnomad AFR exome

AF:

0.0215

Gnomad AMR exome

AF:

0.000924

Gnomad ASJ exome

AF:

0.000117

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000401

Gnomad NFE exome

AF:

0.0000793

Gnomad OTH exome

AF:

0.000678

GnomAD4 exome

AF:

0.000604

AC:

846

AN:

1400346

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

372

AN XY:

691324

show subpopulations

African (AFR)

AF:

0.0202

AC:

648

AN:

32090

American (AMR)

AF:

0.000836

AC:

AN:

35892

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25210

East Asian (EAS)

AF:

0.00

AC:

AN:

36470

South Asian (SAS)

AF:

0.000113

AC:

AN:

79760

European-Finnish (FIN)

AF:

0.000197

AC:

AN:

45580

Middle Eastern (MID)

AF:

0.00193

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.0000629

AC:

AN:

1081464

Other (OTH)

AF:

0.00122

AC:

AN:

58176

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

112

167

223

279

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.00606

AC:

923

AN:

152384

Hom.:

Cov.:

AF XY:

0.00573

AC XY:

427

AN XY:

74514

show subpopulations

African (AFR)

AF:

0.0213

AC:

887

AN:

41592

American (AMR)

AF:

0.00131

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68044

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

140

187

234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00185

Hom.:

Bravo

AF:

0.00622

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Gorlin syndrome (3)

not provided (2)

Gorlin syndrome;C1835820:Holoprosencephaly 7;C2751544:Basal cell carcinoma, susceptibility to, 1 (1)

Hereditary cancer-predisposing syndrome (1)

Holoprosencephaly 7 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

4.8

(source)

DANN

Benign

0.69

PhyloP100

-0.29

Mutation Taster

=99/1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs62637630

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