rs28485160

Positions:

• chr9-95443363-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000264.5(PTCH1):​c.*3030A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 152,428 control chromosomes in the GnomAD database, including 5,004 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.19 (5004 hom., cov: 32)
  • Exomes 𝑓: 0.073 (0 hom.)
• Consequence: PTCH1 NM_000264.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -1.11

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 9-95443363-T-C is Benign according to our data. Variant chr9-95443363-T-C is described in ClinVar as [Benign]. Clinvar id is 367623.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH1	NM_000264.5	c.*3030A>G		3_prime_UTR_variant	24/24	ENST00000331920.11
PTCH1	NM_001083603.3	c.*3030A>G		3_prime_UTR_variant	24/24	ENST00000437951.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11	c.*3030A>G		3_prime_UTR_variant	24/24	5	NM_000264.5	A2
PTCH1	ENST00000437951.6	c.*3030A>G		3_prime_UTR_variant	24/24	5	NM_001083603.3

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29322 AN: 152008 Hom.: 4988 Cov.: 32

Gnomad AFR AF: 0.457

Gnomad AMI AF: 0.0352

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.0366

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.0820

Gnomad FIN AF: 0.0967

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0888

Gnomad OTH AF: 0.148

GnomAD4 exome AF: 0.0728 AC: 22 AN: 302 Hom.: 0 Cov.: 0 AF XY: 0.0765 AC XY: 13 AN XY: 170

Gnomad4 FIN exome AF: 0.0733

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.193 AC: 29402 AN: 152126 Hom.: 5004 Cov.: 32 AF XY: 0.189 AC XY: 14081 AN XY: 74398

Gnomad4 AFR AF: 0.457

Gnomad4 AMR AF: 0.106

Gnomad4 ASJ AF: 0.0366

Gnomad4 EAS AF: 0.166

Gnomad4 SAS AF: 0.0823

Gnomad4 FIN AF: 0.0967

Gnomad4 NFE AF: 0.0888

Gnomad4 OTH AF: 0.154

Alfa AF: 0.156 Hom.: 752

Bravo AF: 0.207

Asia WGS AF: 0.169 AC: 587 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Gorlin syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Holoprosencephaly 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.44
DANN	Benign	0.60

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: rs28485160; hg19: chr9-98205645;