NM_000264.5:c.395-8079A>C

Variant names:

• chr9-95493953-T-G
• rs473902
• NM_000264.5:c.395-8079A>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.395-8079A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.056 in 151,862 control chromosomes in the GnomAD database, including 313 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 0.056 (313 hom., cov: 32)
• Consequence: PTCH1 NM_000264.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18
• Publications: 40 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=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0844 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.395-8079A>C		intron_variant	Intron 2 of 23	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.392-8079A>C		intron_variant	Intron 2 of 23	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.395-8079A>C		intron_variant	Intron 2 of 23	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.392-8079A>C		intron_variant	Intron 2 of 23	5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes AF: 0.0560 AC: 8500 AN: 151740 Hom.: 314 Cov.: 32

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.0472

Gnomad ASJ AF: 0.0389

Gnomad EAS AF: 0.000585

Gnomad SAS AF: 0.00764

Gnomad FIN AF: 0.0904

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0863

Gnomad OTH AF: 0.0493

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

GnomAD4 genome AF: 0.0560 AC: 8499 AN: 151862 Hom.: 313 Cov.: 32 AF XY: 0.0550 AC XY: 4083 AN XY: 74238

African (AFR) AF: 0.0140 AC: 579 AN: 41482

American (AMR) AF: 0.0472 AC: 720 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0389 AC: 135 AN: 3470

East Asian (EAS) AF: 0.000586 AC: 3 AN: 5116

South Asian (SAS) AF: 0.00785 AC: 37 AN: 4714

European-Finnish (FIN) AF: 0.0904 AC: 957 AN: 10582

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0862 AC: 5857 AN: 67916

Other (OTH) AF: 0.0488 AC: 103 AN: 2110

Alfa AF: 0.0728 Hom.: 1240

Bravo AF: 0.0515

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	10
DANN	Benign	0.49
PhyloP100		1.2
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: rs473902; hg19: chr9-98256235;