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rs146447673

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The NM_000264.5(PTCH1):c.4151C>T(p.Pro1384Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,613,488 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P1384P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000042 ( 1 hom. )

Consequence

PTCH1
NM_000264.5 missense

Scores

4
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 1.25
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PP2
Missense variant where missense usually causes diseases, PTCH1
BP4
Computational evidence support a benign effect (MetaRNN=0.08969784).
BP6
Variant 9-95447105-G-A is Benign according to our data. Variant chr9-95447105-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 569000.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.
BS2
High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PTCH1NM_000264.5 linkuse as main transcriptc.4151C>T p.Pro1384Leu missense_variant 23/24 ENST00000331920.11
PTCH1NM_001083603.3 linkuse as main transcriptc.4148C>T p.Pro1383Leu missense_variant 23/24 ENST00000437951.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PTCH1ENST00000331920.11 linkuse as main transcriptc.4151C>T p.Pro1384Leu missense_variant 23/245 NM_000264.5 A2Q13635-1
PTCH1ENST00000437951.6 linkuse as main transcriptc.4148C>T p.Pro1383Leu missense_variant 23/245 NM_001083603.3 Q13635-2

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152180
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000621
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000281
AC:
7
AN:
248720
Hom.:
1
AF XY:
0.0000296
AC XY:
4
AN XY:
135076
show subpopulations
Gnomad AFR exome
AF:
0.0000637
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000131
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000424
AC:
62
AN:
1461308
Hom.:
1
Cov.:
30
AF XY:
0.0000426
AC XY:
31
AN XY:
726990
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000387
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152180
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000621
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000453
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000247
AC:
3
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Gorlin syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingSt. Jude Molecular Pathology, St. Jude Children's Research HospitalDec 08, 2022The PTCH1 c.4151C>T (p.Pro1384Leu) missense change has a maximum subpopulation frequency of 0.013% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with nevoid basal cell carcinoma syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
Benign, criteria provided, single submitterclinical testingInvitaeJan 26, 2024- -
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMar 18, 2021This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.17
Cadd
Benign
19
Dann
Uncertain
0.98
DEOGEN2
Benign
0.26
T;.;.;.;.;.;.
Eigen
Benign
-0.59
Eigen_PC
Benign
-0.62
FATHMM_MKL
Benign
0.49
N
LIST_S2
Uncertain
0.88
D;.;D;D;.;.;D
M_CAP
Benign
0.045
D
MetaRNN
Benign
0.090
T;T;T;T;T;T;T
MetaSVM
Benign
-0.40
T
MutationAssessor
Benign
1.8
L;.;.;.;.;.;.
MutationTaster
Benign
1.0
N;N;N;N;N;N;N
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
-1.2
N;N;N;N;N;N;N
REVEL
Benign
0.22
Sift
Uncertain
0.018
D;D;D;D;D;D;D
Sift4G
Benign
0.086
T;T;T;T;T;T;T
Polyphen
0.26
B;.;.;D;D;.;B
Vest4
0.36
MVP
0.55
MPC
0.079
ClinPred
0.072
T
GERP RS
3.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.077
gMVP
0.31

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs146447673; hg19: chr9-98209387; COSMIC: COSV99045633; API