chr9-95508364-T-TGCCGCCGCC

Variant names:

• chr9-95508364-T-TGCCGCCGCC
• rs71366293
• NM_000264.5:c.-12_-4dupGGCGGCGGC

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_000264.5(PTCH1):​c.-12_-4dupGGCGGCGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000301 in 1,163,698 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000081 (0 hom., cov: 22)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: PTCH1 NM_000264.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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 -12 ACMG points.

• BP6: Variant 9-95508364-T-TGCCGCCGCC is Benign according to our data. Variant chr9-95508364-T-TGCCGCCGCC is described in ClinVar as Likely_benign. ClinVar VariationId is 418688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 12 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.-12_-4dupGGCGGCGGC		5_prime_UTR	Exon 1 of 24	NP_000255.2
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.199-1774_199-1766dupGGCGGCGGC		intron	N/A	NP_001077072.1
	PTCH1	NM_001354918.2		c.-12_-4dupGGCGGCGGC		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.-12_-4dupGGCGGCGGC		5_prime_UTR	Exon 1 of 24	ENSP00000332353.6
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.199-1774_199-1766dupGGCGGCGGC		intron	N/A	ENSP00000389744.2
	PTCH1	ENST00000468211.6	TSL:1	c.4-1774_4-1766dupGGCGGCGGC		intron	N/A	ENSP00000449745.1

Frequencies

GnomAD3 genomes AF: 0.0000812 AC: 12 AN: 147736 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000201

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: 0.0000301

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 23 AN: 1015962 Hom.: 0 Cov.: 30 AF XY: 0.0000229 AC XY: 11 AN XY: 480704

African (AFR) AF: 0.0000992 AC: 2 AN: 20162

American (AMR) AF: 0.000151 AC: 1 AN: 6622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11094

East Asian (EAS) AF: 0.0000479 AC: 1 AN: 20892

South Asian (SAS) AF: 0.0000525 AC: 1 AN: 19040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18176

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2568

European-Non Finnish (NFE) AF: 0.0000193 AC: 17 AN: 878572

Other (OTH) AF: 0.0000257 AC: 1 AN: 38836

GnomAD4 genome AF: 0.0000812 AC: 12 AN: 147736 Hom.: 0 Cov.: 22 AF XY: 0.0000973 AC XY: 7 AN XY: 71922

African (AFR) AF: 0.000172 AC: 7 AN: 40630

American (AMR) AF: 0.000201 AC: 3 AN: 14932

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3398

East Asian (EAS) AF: 0.00 AC: 0 AN: 4964

South Asian (SAS) AF: 0.00 AC: 0 AN: 4754

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000301 AC: 2 AN: 66442

Other (OTH) AF: 0.00 AC: 0 AN: 2024

Alfa AF: 0.0000897 Hom.: 138

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=98/2	polymorphism

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;