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

Variant names:

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

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_-4delGGCGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,163,744 control chromosomes in the GnomAD database, including 127 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0091 (11 hom., cov: 22)
  • Exomes 𝑓: 0.014 (116 hom.)
• Consequence: PTCH1 NM_000264.5 5_prime_UTR
• Clinical Significance: Benign/Likely 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-TGCCGCC-T is Benign according to our data. Variant chr9-95508364-TGCCGCC-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193070.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 = 0.00908 (1343/147830) while in subpopulation SAS AF = 0.0139 (66/4750). AF 95% confidence interval is 0.0129. There are 11 homozygotes in GnomAd4. There are 574 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1343 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_-4delGGCGGC		5_prime_UTR	Exon 1 of 24	NP_000255.2
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.199-1771_199-1766delGGCGGC		intron	N/A	NP_001077072.1
	PTCH1	NM_001354918.2		c.-9_-4delGGCGGC		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_-4delGGCGGC		5_prime_UTR	Exon 1 of 24	ENSP00000332353.6
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.199-1771_199-1766delGGCGGC		intron	N/A	ENSP00000389744.2
	PTCH1	ENST00000468211.6	TSL:1	c.4-1771_4-1766delGGCGGC		intron	N/A	ENSP00000449745.1

Frequencies

GnomAD3 genomes AF: 0.00910 AC: 1345 AN: 147724 Hom.: 11 Cov.: 22

Gnomad AFR AF: 0.00428

Gnomad AMI AF: 0.00112

Gnomad AMR AF: 0.00784

Gnomad ASJ AF: 0.0103

Gnomad EAS AF: 0.000201

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.00181

Gnomad MID AF: 0.0226

Gnomad NFE AF: 0.0136

Gnomad OTH AF: 0.0109

GnomAD2 exomes AF: 0.0141 AC: 21 AN: 1492 AF XY: 0.0174

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0166

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0137 AC: 13923 AN: 1015914 Hom.: 116 AF XY: 0.0135 AC XY: 6505 AN XY: 480676

African (AFR) AF: 0.00337 AC: 68 AN: 20162

American (AMR) AF: 0.00680 AC: 45 AN: 6618

Ashkenazi Jewish (ASJ) AF: 0.0105 AC: 116 AN: 11092

East Asian (EAS) AF: 0.0000957 AC: 2 AN: 20892

South Asian (SAS) AF: 0.0119 AC: 227 AN: 19036

European-Finnish (FIN) AF: 0.00341 AC: 62 AN: 18172

Middle Eastern (MID) AF: 0.0230 AC: 59 AN: 2568

European-Non Finnish (NFE) AF: 0.0146 AC: 12836 AN: 878538

Other (OTH) AF: 0.0131 AC: 508 AN: 38836

GnomAD4 genome AF: 0.00908 AC: 1343 AN: 147830 Hom.: 11 Cov.: 22 AF XY: 0.00797 AC XY: 574 AN XY: 72028

African (AFR) AF: 0.00427 AC: 174 AN: 40742

American (AMR) AF: 0.00783 AC: 117 AN: 14950

Ashkenazi Jewish (ASJ) AF: 0.0103 AC: 35 AN: 3398

East Asian (EAS) AF: 0.000202 AC: 1 AN: 4948

South Asian (SAS) AF: 0.0139 AC: 66 AN: 4750

European-Finnish (FIN) AF: 0.00181 AC: 17 AN: 9392

Middle Eastern (MID) AF: 0.0241 AC: 7 AN: 290

European-Non Finnish (NFE) AF: 0.0136 AC: 903 AN: 66424

Other (OTH) AF: 0.0108 AC: 22 AN: 2046

Alfa AF: 0.00251 Hom.: 138

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	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		=296/4	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;