NM_000264.5:c.-9_-4dupGGCGGC

Variant names:

• chr9-95508364-T-TGCCGCC
• rs71366293
• NM_000264.5:c.-9_-4dupGGCGGC

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.-9_-4dupGGCGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000961 in 1,163,802 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (4 hom., cov: 22)
  • Exomes 𝑓: 0.00058 (1 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-T-TGCCGCC is Benign according to our data. Variant chr9-95508364-T-TGCCGCC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00356 (527/147840) while in subpopulation AFR AF = 0.0114 (464/40744). AF 95% confidence interval is 0.0105. There are 4 homozygotes in GnomAd4. There are 253 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 527 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.-9_-4dupGGCGGC		5_prime_UTR	Exon 1 of 24	NP_000255.2
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.199-1771_199-1766dupGGCGGC		intron	N/A	NP_001077072.1
	PTCH1	NM_001354918.2		c.-9_-4dupGGCGGC		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.-9_-4dupGGCGGC		5_prime_UTR	Exon 1 of 24	ENSP00000332353.6
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.199-1771_199-1766dupGGCGGC		intron	N/A	ENSP00000389744.2
	PTCH1	ENST00000468211.6	TSL:1	c.4-1771_4-1766dupGGCGGC		intron	N/A	ENSP00000449745.1

Frequencies

GnomAD3 genomes AF: 0.00356 AC: 526 AN: 147734 Hom.: 4 Cov.: 22

Gnomad AFR AF: 0.0114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000804

Gnomad ASJ AF: 0.00353

Gnomad EAS AF: 0.000403

Gnomad SAS AF: 0.000210

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000482

Gnomad OTH AF: 0.00247

GnomAD2 exomes AF: 0.000670 AC: 1 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: 0.000790

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000582 AC: 591 AN: 1015962 Hom.: 1 Cov.: 30 AF XY: 0.000530 AC XY: 255 AN XY: 480704

African (AFR) AF: 0.0106 AC: 213 AN: 20160

American (AMR) AF: 0.00106 AC: 7 AN: 6622

Ashkenazi Jewish (ASJ) AF: 0.00334 AC: 37 AN: 11094

East Asian (EAS) AF: 0.000239 AC: 5 AN: 20892

South Asian (SAS) AF: 0.000315 AC: 6 AN: 19040

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

Middle Eastern (MID) AF: 0.000779 AC: 2 AN: 2568

European-Non Finnish (NFE) AF: 0.000321 AC: 282 AN: 878574

Other (OTH) AF: 0.00100 AC: 39 AN: 38836

GnomAD4 genome AF: 0.00356 AC: 527 AN: 147840 Hom.: 4 Cov.: 22 AF XY: 0.00351 AC XY: 253 AN XY: 72036

African (AFR) AF: 0.0114 AC: 464 AN: 40744

American (AMR) AF: 0.000736 AC: 11 AN: 14952

Ashkenazi Jewish (ASJ) AF: 0.00353 AC: 12 AN: 3398

East Asian (EAS) AF: 0.000404 AC: 2 AN: 4948

South Asian (SAS) AF: 0.000210 AC: 1 AN: 4752

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9390

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

European-Non Finnish (NFE) AF: 0.000482 AC: 32 AN: 66430

Other (OTH) AF: 0.00244 AC: 5 AN: 2046

Alfa AF: 0.000179 Hom.: 138

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Gorlin syndrome (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=100/0	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;