9-95447417-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_000264.5(PTCH1):​c.3839C>G​(p.Ser1280Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000414 in 1,450,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1280L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000041 ( 0 hom. )

Consequence

PTCH1
NM_000264.5 missense

Scores

4
15

Clinical Significance

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

Conservation

PhyloP100: 0.653
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 Benign. Variant got -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.11429381).
BP6
Variant 9-95447417-G-C is Benign according to our data. Variant chr9-95447417-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1735401.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
BS2
High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PTCH1NM_000264.5 linkc.3839C>G p.Ser1280Trp missense_variant Exon 23 of 24 ENST00000331920.11 NP_000255.2 Q13635-1
PTCH1NM_001083603.3 linkc.3836C>G p.Ser1279Trp missense_variant Exon 23 of 24 ENST00000437951.6 NP_001077072.1 Q13635-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PTCH1ENST00000331920.11 linkc.3839C>G p.Ser1280Trp missense_variant Exon 23 of 24 5 NM_000264.5 ENSP00000332353.6 Q13635-1
PTCH1ENST00000437951.6 linkc.3836C>G p.Ser1279Trp missense_variant Exon 23 of 24 5 NM_001083603.3 ENSP00000389744.2 Q13635-2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000417
AC:
1
AN:
239534
Hom.:
0
AF XY:
0.00000766
AC XY:
1
AN XY:
130612
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000916
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000414
AC:
6
AN:
1450538
Hom.:
0
Cov.:
33
AF XY:
0.00000416
AC XY:
3
AN XY:
720830
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000452
Gnomad4 OTH exome
AF:
0.0000167
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.00000825
AC:
1

ClinVar

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

Submissions by phenotype

Basal cell nevus syndrome 1 Uncertain:1
Feb 05, 2025
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The PTCH1 c.3839C>G (p.Ser1280Trp) missense change has a maximum subpopulation frequency of 0.00092% 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. -

Hereditary cancer-predisposing syndrome Uncertain:1
May 26, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.S1280W variant (also known as c.3839C>G), located in coding exon 23 of the PTCH1 gene, results from a C to G substitution at nucleotide position 3839. The serine at codon 1280 is replaced by tryptophan, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Gorlin syndrome Benign:1
Dec 08, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
0.0055
T
BayesDel_noAF
Benign
-0.23
CADD
Benign
15
DANN
Uncertain
0.98
DEOGEN2
Benign
0.36
T;.;.;.;.;.;.
Eigen
Benign
-0.84
Eigen_PC
Benign
-0.93
FATHMM_MKL
Benign
0.30
N
LIST_S2
Benign
0.80
T;.;T;T;.;.;T
M_CAP
Uncertain
0.17
D
MetaRNN
Benign
0.11
T;T;T;T;T;T;T
MetaSVM
Uncertain
-0.27
T
MutationAssessor
Benign
0.81
L;.;.;.;.;.;.
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-1.3
N;N;N;N;N;N;N
REVEL
Benign
0.18
Sift
Benign
0.051
T;T;T;T;T;T;D
Sift4G
Uncertain
0.017
D;D;D;D;D;D;D
Polyphen
0.0
B;.;.;D;D;.;B
Vest4
0.30
MutPred
0.18
Loss of glycosylation at S1280 (P = 0.0117);.;.;.;.;.;.;
MVP
0.62
MPC
0.27
ClinPred
0.32
T
GERP RS
-0.33
Varity_R
0.063
gMVP
0.24

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: rs201595274; hg19: chr9-98209699; API