9-95508364-TGCCGCCGCCGCC-TGCCGCCGCCGCCGCC

Variant names:

• chr9-95508364-T-TGCC
• rs71366293
• NM_000264.5:c.-6_-4dupGGC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000264.5(PTCH1):​c.-6_-4dupGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 1,163,256 control chromosomes in the GnomAD database, including 22,394 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4253 hom., cov: 22)
  • Exomes 𝑓: 0.21 (18141 hom.)
• Consequence: PTCH1 NM_000264.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 3.30
• Publications: 2 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 -16 ACMG points.

• BP6: Variant 9-95508364-T-TGCC is Benign according to our data. Variant chr9-95508364-T-TGCC is described in ClinVar as Benign. ClinVar VariationId is 132684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.276 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH1	NM_000264.5	MANE Select	c.-6_-4dupGGC		5_prime_UTR	Exon 1 of 24	NP_000255.2
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.199-1768_199-1766dupGGC		intron	N/A	NP_001077072.1
	PTCH1	NM_001354918.2		c.-6_-4dupGGC		5_prime_UTR	Exon 1 of 23	NP_001341847.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH1	ENST00000331920.11	TSL:5 MANE Select	c.-6_-4dupGGC		5_prime_UTR	Exon 1 of 24	ENSP00000332353.6
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.199-1768_199-1766dupGGC		intron	N/A	ENSP00000389744.2
	PTCH1	ENST00000468211.6	TSL:1	c.4-1768_4-1766dupGGC		intron	N/A	ENSP00000449745.1

Frequencies

GnomAD3 genomes AF: 0.235 AC: 34642 AN: 147642 Hom.: 4237 Cov.: 22

Gnomad AFR AF: 0.280

Gnomad AMI AF: 0.201

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.292

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.219

GnomAD2 exomes AF: 0.119 AC: 177 AN: 1492 AF XY: 0.117

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0500

Gnomad FIN exome AF: 0.0313

Gnomad NFE exome AF: 0.129

Gnomad OTH exome AF: 0.211

GnomAD4 exome AF: 0.205 AC: 208647 AN: 1015512 Hom.: 18141 Cov.: 30 AF XY: 0.205 AC XY: 98564 AN XY: 480486

African (AFR) AF: 0.261 AC: 5255 AN: 20156

American (AMR) AF: 0.0920 AC: 609 AN: 6616

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 2589 AN: 11074

East Asian (EAS) AF: 0.151 AC: 3158 AN: 20856

South Asian (SAS) AF: 0.166 AC: 3161 AN: 19036

European-Finnish (FIN) AF: 0.176 AC: 3201 AN: 18146

Middle Eastern (MID) AF: 0.188 AC: 481 AN: 2562

European-Non Finnish (NFE) AF: 0.208 AC: 182555 AN: 878254

Other (OTH) AF: 0.197 AC: 7638 AN: 38812

GnomAD4 genome AF: 0.235 AC: 34683 AN: 147744 Hom.: 4253 Cov.: 22 AF XY: 0.233 AC XY: 16780 AN XY: 71992

African (AFR) AF: 0.280 AC: 11412 AN: 40706

American (AMR) AF: 0.146 AC: 2190 AN: 14950

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 993 AN: 3396

East Asian (EAS) AF: 0.227 AC: 1122 AN: 4940

South Asian (SAS) AF: 0.166 AC: 789 AN: 4750

European-Finnish (FIN) AF: 0.258 AC: 2416 AN: 9382

Middle Eastern (MID) AF: 0.210 AC: 61 AN: 290

European-Non Finnish (NFE) AF: 0.227 AC: 15058 AN: 66394

Other (OTH) AF: 0.226 AC: 463 AN: 2046

Alfa AF: 0.0927 Hom.: 138

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	1	Gorlin syndrome (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	PTCH1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs71366293; hg19: chr9-98270646; COSMIC: COSV100108942;