rs2297088

Variant names:

• chr9-95480702-G-A
• rs2297088
• NM_000264.5:c.747-114C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000264.5(PTCH1):​c.747-114C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 1,052,920 control chromosomes in the GnomAD database, including 75,016 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (15993 hom., cov: 31)
  • Exomes 𝑓: 0.36 (59023 hom.)
• Consequence: PTCH1 NM_000264.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.533

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 9-95480702-G-A is Benign according to our data. Variant chr9-95480702-G-A is described in ClinVar as [Benign]. Clinvar id is 677031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.747-114C>T		intron_variant	Intron 5 of 23	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.744-114C>T		intron_variant	Intron 5 of 23	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.747-114C>T		intron_variant	Intron 5 of 23	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.744-114C>T		intron_variant	Intron 5 of 23	5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes AF: 0.433 AC: 65712 AN: 151780 Hom.: 15939 Cov.: 31

Gnomad AFR AF: 0.658

Gnomad AMI AF: 0.418

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.404

Gnomad EAS AF: 0.341

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.378

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.367

Gnomad OTH AF: 0.389

GnomAD4 exome AF: 0.355 AC: 320246 AN: 901022 Hom.: 59023 AF XY: 0.352 AC XY: 164034 AN XY: 465596

Gnomad4 AFR exome AF: 0.669

Gnomad4 AMR exome AF: 0.197

Gnomad4 ASJ exome AF: 0.405

Gnomad4 EAS exome AF: 0.318

Gnomad4 SAS exome AF: 0.266

Gnomad4 FIN exome AF: 0.370

Gnomad4 NFE exome AF: 0.363

Gnomad4 OTH exome AF: 0.363

GnomAD4 genome AF: 0.433 AC: 65828 AN: 151898 Hom.: 15993 Cov.: 31 AF XY: 0.427 AC XY: 31659 AN XY: 74220

Gnomad4 AFR AF: 0.659

Gnomad4 AMR AF: 0.261

Gnomad4 ASJ AF: 0.404

Gnomad4 EAS AF: 0.341

Gnomad4 SAS AF: 0.253

Gnomad4 FIN AF: 0.378

Gnomad4 NFE AF: 0.367

Gnomad4 OTH AF: 0.394

Alfa AF: 0.419 Hom.: 1759

Bravo AF: 0.435

Asia WGS AF: 0.326 AC: 1134 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.5
DANN	Benign	0.72

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: rs2297088; hg19: chr9-98242984; COSMIC: COSV59468023; COSMIC: COSV59468023;