9-95508310-TGCCGCCGCC-T

Variant names:

• chr9-95508310-TGCCGCCGCC-T
• rs756897237
• NM_000264.5:c.43_51delGGCGGCGGC

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3 BP6 BS2

The NM_000264.5(PTCH1):​c.43_51delGGCGGCGGC​(p.Gly15_Gly17del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,399,428 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G15G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000060 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: PTCH1 NM_000264.5 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 2.27
• Publications: 5 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: Likely_benign. The variant received -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_000264.5
• BP6: Variant 9-95508310-TGCCGCCGCC-T is Benign according to our data. Variant chr9-95508310-TGCCGCCGCC-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 188284.
• BS2: High AC in GnomAd4 at 9 AD gene.

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.43_51delGGCGGCGGC	p.Gly15_Gly17del	conservative_inframe_deletion	Exon 1 of 24	NP_000255.2
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.199-1720_199-1712delGGCGGCGGC		intron	N/A	NP_001077072.1
	PTCH1	NM_001354918.2		c.43_51delGGCGGCGGC	p.Gly15_Gly17del	conservative_inframe_deletion	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.43_51delGGCGGCGGC	p.Gly15_Gly17del	conservative_inframe_deletion	Exon 1 of 24	ENSP00000332353.6
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.199-1720_199-1712delGGCGGCGGC		intron	N/A	ENSP00000389744.2
	PTCH1	ENST00000468211.6	TSL:1	c.4-1720_4-1712delGGCGGCGGC		intron	N/A	ENSP00000449745.1

Frequencies

GnomAD3 genomes AF: 0.0000597 AC: 9 AN: 150744 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000329

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000444

Gnomad OTH AF: 0.000484

GnomAD2 exomes AF: 0.000368 AC: 8 AN: 21730 AF XY: 0.000637

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.00313

GnomAD4 exome AF: 0.000110 AC: 137 AN: 1248574 Hom.: 1 AF XY: 0.0000969 AC XY: 59 AN XY: 608970

African (AFR) AF: 0.00 AC: 0 AN: 24394

American (AMR) AF: 0.000563 AC: 8 AN: 14198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17570

East Asian (EAS) AF: 0.00 AC: 0 AN: 28922

South Asian (SAS) AF: 0.00 AC: 0 AN: 57180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35786

Middle Eastern (MID) AF: 0.000566 AC: 2 AN: 3536

European-Non Finnish (NFE) AF: 0.000123 AC: 125 AN: 1015750

Other (OTH) AF: 0.0000390 AC: 2 AN: 51238

GnomAD4 genome AF: 0.0000597 AC: 9 AN: 150854 Hom.: 0 Cov.: 32 AF XY: 0.0000407 AC XY: 3 AN XY: 73690

African (AFR) AF: 0.00 AC: 0 AN: 41332

American (AMR) AF: 0.000329 AC: 5 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5092

South Asian (SAS) AF: 0.00 AC: 0 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000444 AC: 3 AN: 67500

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000567

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Gorlin syndrome (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not provided (1)
-	-	1	PTCH1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.3
Mutation Taster		=186/14	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs756897237; hg19: chr9-98270592;