dbSNP rs752765582: PTCH1:p.Glu2AsnfsTer9 (chr9-95516816-TC-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PVS1BS2

The NM_001083603.3(PTCH1):c.4delG(p.Glu2AsnfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000475 in 1,600,974 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

PTCH1
NM_001083603.3 frameshift

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 2.13

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]

PTCH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 212 pathogenic variants in the truncated region.

BS2

High AC in GnomAdExome4 at 72 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_001083603.3 link	c.4delG	p.Glu2AsnfsTer9	frameshift_variant	Exon 1 of 24	ENST00000437951.6	NP_001077072.1	Q13635-2
PTCH1	NM_001083602.3 link	c.-346delG		5_prime_UTR_variant	Exon 1 of 24		NP_001077071.1	Q13635-3
PTCH1	NM_001354919.2 link	c.-346delG		5_prime_UTR_variant	Exon 1 of 5		NP_001341848.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000437951.6 link	c.4delG	p.Glu2AsnfsTer9	frameshift_variant	Exon 1 of 24	5	NM_001083603.3	ENSP00000389744.2		Q13635-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000295

AC:

AN:

237406

Hom.:

AF XY:

0.0000310

AC XY:

AN XY:

129092

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000309

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000364

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000497

AC:

AN:

1448856

Hom.:

Cov.:

AF XY:

0.0000500

AC XY:

AN XY:

720102

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000387

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000533

Gnomad4 OTH exome

AF:

0.0000501

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000302

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Gorlin syndrome

Pathogenic:1

Mar 08, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Anophthalmia-microphthalmia syndrome

Pathogenic:1

Jan 01, 2013

Paul Sabatier University EA-4555, Paul Sabatier University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

rare variant, functional studies demonstrating is deleterious effect on protein. -

Gorlin syndrome;C1835820:Holoprosencephaly 7

Uncertain:1

Jun 07, 2021

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The inherited heterozygous PTCH1 variant c.4delG (p.Glu2AsnfsTer9) is localized in coding exon 1 of 23 which is unique to one of the longer transcripts (NM_001083603.2, isoform L′ from transcript 1a′; PMID: 29930296). This isoform was previously found to be expressed at very low levels in multiple human tissues (PMID: 15780749). In the other longer PTCH1 transcripts, this variant is present in the non-coding 5’ UTR region. This variant is predicted to alter the translational reading frame and cause loss of normal protein function either through protein truncationor nonsense-mediated mRNA decay. The c.4delG variant has been reported once in an individual with ocular anomalies - microphthalmia, cataract, and sclerocornea (PMID: 26893459). Ocular developmental anomalies can be seen as part of both the basal cell nevus syndrome and Holoprosencephaly phenotypes. This variant is present at a very low frequency (0.00002630, 4/152118 heterozygous alleles, no homozygotes) in gnomAD v3 indicating it is not a common benign variant in the populations represented in this database. Due to lack of additional genetic and functional evidence, the inherited heterozygous c.4delG (p.Glu2AsnfsTer9) variant seen in one of the alternate exons unique to a single transcript of PTCH1 gene is reported as a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome

Benign:1

Jun 14, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over