rs780434261

chr9-95476776-T-Achr9-95476776-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000264.5(PTCH1):c.1585A>T(p.Lys529Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTCH1 NM_000264.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.37

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-95476776-T-A is Pathogenic according to our data. Variant chr9-95476776-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 379879.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-95476776-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH1	NM_000264.5	c.1585A>T	p.Lys529Ter	stop_gained	11/24	ENST00000331920.11
PTCH1	NM_001083603.3	c.1582A>T	p.Lys528Ter	stop_gained	11/24	ENST00000437951.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11	c.1585A>T	p.Lys529Ter	stop_gained	11/24	5	NM_000264.5	A2
PTCH1	ENST00000437951.6	c.1582A>T	p.Lys528Ter	stop_gained	11/24	5	NM_001083603.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 29, 2016

The K529X nonsense variant in the PTCH1 gene has been reported previouslyin association with Gorlin syndrome (Huang et al., 2013; Hasenpusch-Theil et al., 1998). Thispathogenic variant is predicted to cause loss of normal protein function either through proteintruncation or nonsense-mediated mRNA decay. The variant was not observed in approximately6,500 individuals of European and African American ancestry in the NHLBI Exome SequencingProject, indicating it is not a common benign variant in these populations. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
Cadd	Pathogenic	42
Dann	Uncertain	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
Vest4		0.97
GERP RS		5.5

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

Other links and lift over

dbSNP: rs780434261; hg19: chr9-98239058; COSMIC: COSV59498127; COSMIC: COSV59498127;