rs2297088

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• basal cell nevus syndrome 1

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• holoprosencephaly 7

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• nevoid basal cell carcinoma syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• holoprosencephaly

  Inheritance: AD Classification: LIMITED Submitted by: Illumina

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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

African (AFR) AF: 0.669 AC: 14714 AN: 21986

American (AMR) AF: 0.197 AC: 7392 AN: 37558

Ashkenazi Jewish (ASJ) AF: 0.405 AC: 9101 AN: 22450

East Asian (EAS) AF: 0.318 AC: 10989 AN: 34564

South Asian (SAS) AF: 0.266 AC: 18857 AN: 70988

European-Finnish (FIN) AF: 0.370 AC: 14560 AN: 39342

Middle Eastern (MID) AF: 0.344 AC: 1451 AN: 4212

European-Non Finnish (NFE) AF: 0.363 AC: 227940 AN: 627918

Other (OTH) AF: 0.363 AC: 15242 AN: 42004

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

African (AFR) AF: 0.659 AC: 27266 AN: 41398

American (AMR) AF: 0.261 AC: 3988 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.404 AC: 1402 AN: 3472

East Asian (EAS) AF: 0.341 AC: 1754 AN: 5142

South Asian (SAS) AF: 0.253 AC: 1217 AN: 4808

European-Finnish (FIN) AF: 0.378 AC: 3979 AN: 10536

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.367 AC: 24910 AN: 67942

Other (OTH) AF: 0.394 AC: 832 AN: 2110

Alfa AF: 0.428 Hom.: 1921

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
PhyloP100		0.53
PromoterAI		0.015	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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