dbSNP rs766227557: PTCH1:p.Tyr820Tyr (chr9-95467216-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_000264.5(PTCH1):c.2460C>T(p.Tyr820Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,611,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

PTCH1
NM_000264.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: -0.250

Publications

1 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, Orphanet, Labcorp Genetics (formerly Invitae)
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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 9-95467216-G-A is Benign according to our data. Variant chr9-95467216-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 367667.

BP7

Synonymous conserved (PhyloP=-0.25 with no splicing effect.

BS2

High AC in GnomAdExome4 at 25 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.2460C>T	p.Tyr820Tyr	synonymous	Exon 15 of 24	NP_000255.2	Q13635-1
PTCH1	NM_001083603.3	MANE Plus Clinical	c.2457C>T	p.Tyr819Tyr	synonymous	Exon 15 of 24	NP_001077072.1	Q13635-2
PTCH1	NM_001354918.2		c.2304C>T	p.Tyr768Tyr	synonymous	Exon 14 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.2460C>T	p.Tyr820Tyr	synonymous	Exon 15 of 24	ENSP00000332353.6	Q13635-1
PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.2457C>T	p.Tyr819Tyr	synonymous	Exon 15 of 24	ENSP00000389744.2	Q13635-2
PTCH1	ENST00000429896.6	TSL:1	c.2007C>T	p.Tyr669Tyr	synonymous	Exon 15 of 24	ENSP00000414823.2	Q13635-4

Frequencies

GnomAD3 genomes

AF:

0.0000134

AC:

AN:

149352

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000248

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000398

AC:

AN:

251488

AF XY:

0.0000515

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461772

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.000112

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000174

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111940

Other (OTH)

AF:

0.0000497

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000134

AC:

AN:

149352

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

72896

show subpopulations

African (AFR)

AF:

0.0000248

AC:

AN:

40382

American (AMR)

AF:

0.00

AC:

AN:

15036

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3426

East Asian (EAS)

AF:

0.00

AC:

AN:

5014

South Asian (SAS)

AF:

0.00

AC:

AN:

4690

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10492

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.0000149

AC:

AN:

67070

Other (OTH)

AF:

0.00

AC:

AN:

2034

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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.:

Bravo

AF:

0.0000151

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Gorlin syndrome (2)

Hereditary cancer-predisposing syndrome (1)

Holoprosencephaly sequence (1)

not specified (1)

PTCH1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

4.7

(source)

DANN

Benign

0.49

PhyloP100

-0.25

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

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