9-95444118-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_000264.5(PTCH1):c.*2275T>A variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.0884 in 148,238 control chromosomes in the GnomAD database, including 1,596 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.089 (1596 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (0 hom.)
• Consequence: PTCH1 NM_000264.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 4.13

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 9-95444118-A-T is Benign according to our data. Variant chr9-95444118-A-T is described in ClinVar as [Benign]. Clinvar id is 367628.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH1	NM_000264.5	c.*2275T>A		3_prime_UTR_variant	24/24	ENST00000331920.11
PTCH1	NM_001083603.3	c.*2275T>A		3_prime_UTR_variant	24/24	ENST00000437951.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11	c.*2275T>A		3_prime_UTR_variant	24/24	5	NM_000264.5	A2
PTCH1	ENST00000437951.6	c.*2275T>A		3_prime_UTR_variant	24/24	5	NM_001083603.3

Frequencies

GnomAD3 genomes AF: 0.0885 AC: 13080 AN: 147758 Hom.: 1592 Cov.: 32

Gnomad AFR AF: 0.280

Gnomad AMI AF: 0.00554

Gnomad AMR AF: 0.0513

Gnomad ASJ AF: 0.0255

Gnomad EAS AF: 0.0207

Gnomad SAS AF: 0.00830

Gnomad FIN AF: 0.00585

Gnomad MID AF: 0.0260

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.0625

GnomAD4 exome AF: 0.00761 AC: 3 AN: 394 Hom.: 0 Cov.: 0 AF XY: 0.0127 AC XY: 3 AN XY: 236

Gnomad4 FIN exome AF: 0.00769

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0887 AC: 13108 AN: 147844 Hom.: 1596 Cov.: 32 AF XY: 0.0872 AC XY: 6275 AN XY: 72000

Gnomad4 AFR AF: 0.280

Gnomad4 AMR AF: 0.0513

Gnomad4 ASJ AF: 0.0255

Gnomad4 EAS AF: 0.0209

Gnomad4 SAS AF: 0.00787

Gnomad4 FIN AF: 0.00585

Gnomad4 NFE AF: 0.0103

Gnomad4 OTH AF: 0.0630

Alfa AF: 0.0747 Hom.: 122

Bravo AF: 0.101

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	-0.42
Cadd	Benign	4.9
Dann	Benign	0.82

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: rs28380046; hg19: chr9-98206400; COSMIC: COSV59466252; COSMIC: COSV59466252;