rs28701981

Variant names:

• chr9-95455299-T-C
• rs28701981
• NM_000264.5:c.3306+977A>G

Variant summary

Our verdict is Benign. The variant received -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
• 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 -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 rank	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.3306+977A>G		intron_variant	Intron 19 of 23	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.3303+977A>G		intron_variant	Intron 19 of 23	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.3306+977A>G		intron_variant	Intron 19 of 23	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.3303+977A>G		intron_variant	Intron 19 of 23	5	NM_001083603.3	ENSP00000389744.2

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

African (AFR) AF: 0.673 AC: 27952 AN: 41512

American (AMR) AF: 0.255 AC: 3902 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 1434 AN: 3464

East Asian (EAS) AF: 0.348 AC: 1799 AN: 5176

South Asian (SAS) AF: 0.254 AC: 1227 AN: 4832

European-Finnish (FIN) AF: 0.375 AC: 3975 AN: 10596

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.361 AC: 24570 AN: 67990

Other (OTH) AF: 0.390 AC: 823 AN: 2108

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
PhyloP100		-1.6
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: rs28701981; hg19: chr9-98217581;