rs28701981

Positions:

• chr9-95455299-T-C

Variant summary

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

The NM_000264.5(PTCH1):​c.3306+977A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.434 in 152,170 control chromosomes in the GnomAD database, including 16,236 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 0.43 (16236 hom., cov: 33)
• Consequence: PTCH1 NM_000264.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.60

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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.667 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH1	NM_000264.5	c.3306+977A>G		intron_variant		ENST00000331920.11
PTCH1	NM_001083603.3	c.3303+977A>G		intron_variant		ENST00000437951.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11	c.3306+977A>G		intron_variant		5	NM_000264.5	A2
PTCH1	ENST00000437951.6	c.3303+977A>G		intron_variant		5	NM_001083603.3

Frequencies

GnomAD3 genomes AF: 0.433 AC: 65874 AN: 152052 Hom.: 16182 Cov.: 33

Gnomad AFR AF: 0.673

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.414

Gnomad EAS AF: 0.348

Gnomad SAS AF: 0.253

Gnomad FIN AF: 0.375

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.361

Gnomad OTH AF: 0.385

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

GnomAD4 genome AF: 0.434 AC: 65991 AN: 152170 Hom.: 16236 Cov.: 33 AF XY: 0.427 AC XY: 31732 AN XY: 74396

Gnomad4 AFR AF: 0.673

Gnomad4 AMR AF: 0.255

Gnomad4 ASJ AF: 0.414

Gnomad4 EAS AF: 0.348

Gnomad4 SAS AF: 0.254

Gnomad4 FIN AF: 0.375

Gnomad4 NFE AF: 0.361

Gnomad4 OTH AF: 0.390

Alfa AF: 0.418 Hom.: 2348

Bravo AF: 0.435

Asia WGS AF: 0.332 AC: 1155 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.016
DANN	Benign	0.45

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: rs28701981; hg19: chr9-98217581;