9-95475514-A-G

Variant names:

• chr9-95475514-A-G
• rs2236407
• NM_000264.5:c.1728+520T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000264.5(PTCH1):​c.1728+520T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 152,092 control chromosomes in the GnomAD database, including 13,172 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.40 (13172 hom., cov: 32)
• Consequence: PTCH1 NM_000264.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.717
• Publications: 8 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.542 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000264.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH1	NM_000264.5	MANE Select	c.1728+520T>C		intron	N/A	NP_000255.2
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.1725+520T>C		intron	N/A	NP_001077072.1
	PTCH1	NM_001354918.2		c.1572+520T>C		intron	N/A	NP_001341847.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH1	ENST00000331920.11	TSL:5 MANE Select	c.1728+520T>C		intron	N/A	ENSP00000332353.6
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.1725+520T>C		intron	N/A	ENSP00000389744.2
	PTCH1	ENST00000429896.6	TSL:1	c.1275+520T>C		intron	N/A	ENSP00000414823.2

Frequencies

GnomAD3 genomes AF: 0.401 AC: 60994 AN: 151974 Hom.: 13119 Cov.: 32

Gnomad AFR AF: 0.547

Gnomad AMI AF: 0.419

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.410

Gnomad EAS AF: 0.343

Gnomad SAS AF: 0.251

Gnomad FIN AF: 0.377

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.367

Gnomad OTH AF: 0.368

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.402 AC: 61105 AN: 152092 Hom.: 13172 Cov.: 32 AF XY: 0.396 AC XY: 29462 AN XY: 74372

African (AFR) AF: 0.548 AC: 22716 AN: 41466

American (AMR) AF: 0.248 AC: 3794 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 1422 AN: 3468

East Asian (EAS) AF: 0.342 AC: 1771 AN: 5174

South Asian (SAS) AF: 0.252 AC: 1215 AN: 4818

European-Finnish (FIN) AF: 0.377 AC: 3990 AN: 10582

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.367 AC: 24928 AN: 67986

Other (OTH) AF: 0.373 AC: 787 AN: 2108

Alfa AF: 0.398 Hom.: 2222

Bravo AF: 0.400

Asia WGS AF: 0.322 AC: 1117 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.1
DANN	Benign	0.66
PhyloP100		-0.72
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2236407; hg19: chr9-98237796;