9-95508364-TGCCGCC-T

Position:

• chr9-95508364-TGCCGCC-T

Variant summary

Our verdict is Benign. Variant got -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:9
• Conservation: PhyloP100: 3.30

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 193070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95508364-TGCCGCC-T is described in Lovd as [Likely_benign]. Variant chr9-95508364-TGCCGCC-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1343 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.-9_-4delGGCGGC		5_prime_UTR_variant	1/24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.199-1771_199-1766delGGCGGC		intron_variant		ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.-9_-4delGGCGGC		5_prime_UTR_variant	1/24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.199-1771_199-1766delGGCGGC		intron_variant		5	NM_001083603.3	ENSP00000389744.2

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

GnomAD3 exomes AF: 0.0141 AC: 21 AN: 1492 Hom.: 0 AF XY: 0.0174 AC XY: 15 AN XY: 862

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad SAS 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

Gnomad4 AFR exome AF: 0.00337

Gnomad4 AMR exome AF: 0.00680

Gnomad4 ASJ exome AF: 0.0105

Gnomad4 EAS exome AF: 0.0000957

Gnomad4 SAS exome AF: 0.0119

Gnomad4 FIN exome AF: 0.00341

Gnomad4 NFE exome AF: 0.0146

Gnomad4 OTH exome AF: 0.0131

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

Gnomad4 AFR AF: 0.00427

Gnomad4 AMR AF: 0.00783

Gnomad4 ASJ AF: 0.0103

Gnomad4 EAS AF: 0.000202

Gnomad4 SAS AF: 0.0139

Gnomad4 FIN AF: 0.00181

Gnomad4 NFE AF: 0.0136

Gnomad4 OTH AF: 0.0108

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 31, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 04, 2021	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PTCH1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 30, 2016	Variant summary: c.-9_-4delGGCGGC affects mildly conserved nucleotides, resulting in a deletion of 6 nucleotides in the 5UTR region. This variant was found in 17/5008 control chromosomes of 1000Gs project at a frequency of 0.0034, which greatly exceeds the maximal expected frequency of a pathogenic allele (0.000017). The variant has been reported as Likely Benign by one reputable databases/clinical laboratories without evidence to independently evaluate. Taking together, the variant was classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 15, 2015

Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign);Other data supporting benign classification -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs71366293; hg19: chr9-98270646;