9-95497421-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000264.5(PTCH1):c.394+8986A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 152,080 control chromosomes in the GnomAD database, including 10,966 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 0.37 (10966 hom., cov: 32)
• Consequence: PTCH1 NM_000264.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.62

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=-0.79).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.485 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH1	NM_000264.5	c.394+8986A>C		intron_variant		ENST00000331920.11
PTCH1	NM_001083603.3	c.391+8986A>C		intron_variant		ENST00000437951.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11	c.394+8986A>C		intron_variant		5	NM_000264.5	A2
PTCH1	ENST00000437951.6	c.391+8986A>C		intron_variant		5	NM_001083603.3

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55855 AN: 151962 Hom.: 10946 Cov.: 32

Gnomad AFR AF: 0.491

Gnomad AMI AF: 0.273

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.361

Gnomad EAS AF: 0.317

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.373

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.340

Gnomad OTH AF: 0.334

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

GnomAD4 genome AF: 0.368 AC: 55931 AN: 152080 Hom.: 10966 Cov.: 32 AF XY: 0.362 AC XY: 26935 AN XY: 74332

Gnomad4 AFR AF: 0.491

Gnomad4 AMR AF: 0.232

Gnomad4 ASJ AF: 0.361

Gnomad4 EAS AF: 0.317

Gnomad4 SAS AF: 0.212

Gnomad4 FIN AF: 0.373

Gnomad4 NFE AF: 0.340

Gnomad4 OTH AF: 0.339

Alfa AF: 0.328 Hom.: 12070

Bravo AF: 0.365

Asia WGS AF: 0.281 AC: 979 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	8.7
Dann	Benign	0.53

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: rs10512248; hg19: chr9-98259703;