NM_000264.5:c.3839C>G

Variant names:

• chr9-95447417-G-C
• rs201595274
• NM_000264.5:c.3839C>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

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. 15/22 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 𝑓: 0.0000041 (0 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.653
• Publications: 7 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 1735401.
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.3839C>G	p.Ser1280Trp	missense_variant	Exon 23 of 24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.3836C>G	p.Ser1279Trp	missense_variant	Exon 23 of 24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.3839C>G	p.Ser1280Trp	missense_variant	Exon 23 of 24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.3836C>G	p.Ser1279Trp	missense_variant	Exon 23 of 24	5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000417 AC: 1 AN: 239534 AF XY: 0.00000766

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33010

American (AMR) AF: 0.00 AC: 0 AN: 43544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25594

East Asian (EAS) AF: 0.00 AC: 0 AN: 39584

South Asian (SAS) AF: 0.00 AC: 0 AN: 85466

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5672

European-Non Finnish (NFE) AF: 0.00000452 AC: 5 AN: 1107192

Other (OTH) AF: 0.0000167 AC: 1 AN: 59868

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

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 05, 2025

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;.;.;.;.;.;.
PhyloP100		0.65
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
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs201595274; hg19: chr9-98209699;