9-95462774-G-T

Variant names:

• chr9-95462774-G-T
• rs28377268
• NM_000264.5:c.2561-776C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_000264.5(PTCH1):​c.2561-776C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 152,114 control chromosomes in the GnomAD database, including 5,804 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 0.22 (5804 hom., cov: 33)
• Consequence: PTCH1 NM_000264.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.01
• Publications: 16 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.482 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.2561-776C>A		intron	N/A	NP_000255.2
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.2558-776C>A		intron	N/A	NP_001077072.1
	PTCH1	NM_001354918.2		c.2405-776C>A		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.2561-776C>A		intron	N/A	ENSP00000332353.6
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.2558-776C>A		intron	N/A	ENSP00000389744.2
	PTCH1	ENST00000429896.6	TSL:1	c.2108-776C>A		intron	N/A	ENSP00000414823.2

Frequencies

GnomAD3 genomes AF: 0.217 AC: 33008 AN: 151994 Hom.: 5780 Cov.: 33

Gnomad AFR AF: 0.487

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.0925

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.170

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

GnomAD4 genome AF: 0.217 AC: 33077 AN: 152114 Hom.: 5804 Cov.: 33 AF XY: 0.212 AC XY: 15771 AN XY: 74382

African (AFR) AF: 0.488 AC: 20198 AN: 41410

American (AMR) AF: 0.121 AC: 1856 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 371 AN: 3470

East Asian (EAS) AF: 0.201 AC: 1040 AN: 5168

South Asian (SAS) AF: 0.0923 AC: 446 AN: 4830

European-Finnish (FIN) AF: 0.104 AC: 1108 AN: 10614

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.112 AC: 7638 AN: 68000

Other (OTH) AF: 0.167 AC: 354 AN: 2116

Alfa AF: 0.0699 Hom.: 92

Bravo AF: 0.232

Asia WGS AF: 0.150 AC: 521 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Uncertain	0.98
PhyloP100		2.0
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: rs28377268; hg19: chr9-98225056;