rs71366293

Variant names:

• chr9-95508364-TGCCGCCGCCGCC-T
• rs71366293
• NM_000264.5:c.-15_-4delGGCGGCGGCGGC

Your query was ambiguous. Multiple possible variants found:

• chr9-95508364-TGCCGCCGCCGCC-T
• chr9-95508364-TGCCGCCGCCGCC-TGCC
• chr9-95508364-TGCCGCCGCCGCC-TGCCGCC
• chr9-95508364-TGCCGCCGCCGCC-TGCCGCCGCC
• chr9-95508364-TGCCGCCGCCGCC-TGCCGCCGCCGCCGCC
• chr9-95508364-TGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCC
• chr9-95508364-TGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCCGCC
• chr9-95508364-TGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCCGCCGCC
• chr9-95508364-TGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCCGCCGCCGCC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000264.5(PTCH1):​c.-15_-4delGGCGGCGGCGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000516 in 1,163,786 control chromosomes in the GnomAD database, including 6 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00076 (2 hom., cov: 22)
  • Exomes 𝑓: 0.00048 (4 hom.)
• Consequence: PTCH1 NM_000264.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• 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-TGCCGCCGCCGCC-T is Benign according to our data. Variant chr9-95508364-TGCCGCCGCCGCC-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 219940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000764 (113/147840) while in subpopulation SAS AF = 0.0227 (108/4750). AF 95% confidence interval is 0.0193. There are 2 homozygotes in GnomAd4. There are 82 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 113 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.-15_-4delGGCGGCGGCGGC		5_prime_UTR	Exon 1 of 24	NP_000255.2
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.199-1777_199-1766delGGCGGCGGCGGC		intron	N/A	NP_001077072.1
	PTCH1	NM_001354918.2		c.-15_-4delGGCGGCGGCGGC		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.-15_-4delGGCGGCGGCGGC		5_prime_UTR	Exon 1 of 24	ENSP00000332353.6
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.199-1777_199-1766delGGCGGCGGCGGC		intron	N/A	ENSP00000389744.2
	PTCH1	ENST00000468211.6	TSL:1	c.4-1777_4-1766delGGCGGCGGCGGC		intron	N/A	ENSP00000449745.1

Frequencies

GnomAD3 genomes AF: 0.000772 AC: 114 AN: 147734 Hom.: 2 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0229

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000452

Gnomad OTH AF: 0.000988

GnomAD2 exomes AF: 0.00 AC: 0 AN: 1492 AF XY: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000480 AC: 488 AN: 1015946 Hom.: 4 AF XY: 0.000539 AC XY: 259 AN XY: 480692

African (AFR) AF: 0.0000496 AC: 1 AN: 20162

American (AMR) AF: 0.00 AC: 0 AN: 6622

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 20892

South Asian (SAS) AF: 0.0209 AC: 397 AN: 19024

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

Middle Eastern (MID) AF: 0.00156 AC: 4 AN: 2568

European-Non Finnish (NFE) AF: 0.0000580 AC: 51 AN: 878572

Other (OTH) AF: 0.000901 AC: 35 AN: 38836

GnomAD4 genome AF: 0.000764 AC: 113 AN: 147840 Hom.: 2 Cov.: 22 AF XY: 0.00114 AC XY: 82 AN XY: 72036

African (AFR) AF: 0.00 AC: 0 AN: 40744

American (AMR) AF: 0.00 AC: 0 AN: 14952

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4948

South Asian (SAS) AF: 0.0227 AC: 108 AN: 4750

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

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

European-Non Finnish (NFE) AF: 0.0000452 AC: 3 AN: 66430

Other (OTH) AF: 0.000978 AC: 2 AN: 2046

Alfa AF: 0.00 Hom.: 138

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	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		=294/6	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;