NM_000264.5:c.4258T>A

Variant names:

• chr9-95446998-A-T
• rs864622068
• NM_000264.5:c.4258T>A
• PTCH1 p.Cys1420Ser

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Moderate

The NM_000264.5(PTCH1):c.4258T>A (p.Cys1420Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.C1420?: Uncertain_significance (ClinVar VariationId 4146850, 1 star); p.C1420G: Uncertain_significance (ClinVar VariationId 1739138, 1 star); p.C1420R: Likely_benign (ClinVar VariationId 219394, 2 stars); p.C1420Y: Uncertain_significance (ClinVar VariationId 1051822, 2 stars)

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.757
• Publications: 0 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, STRONG Submitted by: G2P, PanelApp Australia
• holoprosencephaly 7

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• nevoid basal cell carcinoma syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, ClinGen
• exstrophy-epispadias complex

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• holoprosencephaly

  Inheritance: AD Classification: LIMITED Submitted by: Illumina, ClinGen

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000264.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PTCH1 NM_000264.5	MANE Select	c.4258T>A p.Cys1420Ser	missense	Exon 23 of 24	Prot: NP_000255.2 UniProt:
	PTCH1 NM_001083603.3	MANE Plus Clinical	c.4255T>A p.Cys1419Ser	missense	Exon 23 of 24	Prot: NP_001077072.1 UniProt:
	PTCH1 NM_001354918.2		c.4102T>A p.Cys1368Ser	missense	Exon 22 of 23	Prot: NP_001341847.1 UniProt:

PTCH1 NM_000264.5

MANE Select

HGVSc / HGVSpc.4258T>Ap.Cys1420Ser

Exon rankExon 23 of 24

missense

Prot: NP_000255.2UniProt: Q13635-1

PTCH1 NM_001083603.3

MANE Plus Clinical

HGVSc / HGVSpc.4255T>Ap.Cys1419Ser

Exon rankExon 23 of 24

missense

Prot: NP_001077072.1UniProt: Q13635-2

PTCH1 NM_001354918.2

HGVSc / HGVSpc.4102T>Ap.Cys1368Ser

Exon rankExon 22 of 23

missense

Prot: NP_001341847.1UniProt: A0A1W5YLI7

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PTCH1 ENST00000331920.11	TSL:5MANE Select	c.4258T>A p.Cys1420Ser	missense	Exon 23 of 24	Prot: ENSP00000332353.6 UniProt:
	PTCH1 ENST00000437951.6	TSL:5MANE Plus Clinical	c.4255T>A p.Cys1419Ser	missense	Exon 23 of 24	Prot: ENSP00000389744.2 UniProt:
	PTCH1 ENST00000429896.6	TSL:1	c.3805T>A p.Cys1269Ser	missense	Exon 23 of 24	Prot: ENSP00000414823.2 UniProt:

PTCH1 ENST00000331920.11

TSL:5MANE Select

HGVSc / HGVSpc.4258T>Ap.Cys1420Ser

Exon rankExon 23 of 24

missense

Prot: ENSP00000332353.6UniProt: Q13635-1

PTCH1 ENST00000437951.6

TSL:5MANE Plus Clinical

HGVSc / HGVSpc.4255T>Ap.Cys1419Ser

Exon rankExon 23 of 24

missense

Prot: ENSP00000389744.2UniProt: Q13635-2

PTCH1 ENST00000429896.6

TSL:1

HGVSc / HGVSpc.3805T>Ap.Cys1269Ser

Exon rankExon 23 of 24

missense

Prot: ENSP00000414823.2UniProt: Q13635-4

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:30
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	10
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	2.3
DANN	Benign	0.42
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.086	N
FuncVEP CTI	Benign	0.020
GPN-Star LLR	N/A	-5.0
GPN-Star score	N/A	5.0
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-0.78	T
Mutation Taster	N/A	89/11	polymorphism
MutationAssessor	Benign	1.7	L
PhyloP100	Benign	0.76
popEVE	Benign	-2.7
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.17
Sift	Benign	0.39	T
Sift4G	Benign	0.51	T
Varity_R	N/A	0.035
VESM-3B	Benign	-1.7

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs864622068;

hg19: chr9-98209280;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar