chr9-95508364-TGCCGCCGCC-T

Position:

• chr9-95508364-TGCCGCCGCC-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_000264.5(PTCH1):​c.-12_-4delGGCGGCGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000637 in 1,163,798 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 22)
  • Exomes 𝑓: 0.00065 (1 hom.)
• Consequence: PTCH1 NM_000264.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• 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 -12 ACMG points.

• BP6: Variant 9-95508364-TGCCGCCGCC-T is Benign according to our data. Variant chr9-95508364-TGCCGCCGCC-T is described in ClinVar as [Likely_benign]. Clinvar id is 215454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 82 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.-12_-4delGGCGGCGGC		5_prime_UTR_variant	1/24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.199-1774_199-1766delGGCGGCGGC		intron_variant		ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.-12_-4delGGCGGCGGC		5_prime_UTR_variant	1/24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.199-1774_199-1766delGGCGGCGGC		intron_variant		5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes AF: 0.000555 AC: 82 AN: 147736 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000271

Gnomad AMI AF: 0.00112

Gnomad AMR AF: 0.000603

Gnomad ASJ AF: 0.00235

Gnomad EAS AF: 0.000604

Gnomad SAS AF: 0.000421

Gnomad FIN AF: 0.00128

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000542

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000670 AC: 1 AN: 1492 Hom.: 0 AF XY: 0.00116 AC XY: 1 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: 0.000790

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000649 AC: 659 AN: 1015956 Hom.: 1 AF XY: 0.000641 AC XY: 308 AN XY: 480704

Gnomad4 AFR exome AF: 0.000446

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00270

Gnomad4 EAS exome AF: 0.000431

Gnomad4 SAS exome AF: 0.000578

Gnomad4 FIN exome AF: 0.000825

Gnomad4 NFE exome AF: 0.000628

Gnomad4 OTH exome AF: 0.000747

GnomAD4 genome AF: 0.000555 AC: 82 AN: 147842 Hom.: 0 Cov.: 22 AF XY: 0.000639 AC XY: 46 AN XY: 72038

Gnomad4 AFR AF: 0.000270

Gnomad4 AMR AF: 0.000602

Gnomad4 ASJ AF: 0.00235

Gnomad4 EAS AF: 0.000606

Gnomad4 SAS AF: 0.000421

Gnomad4 FIN AF: 0.00128

Gnomad4 NFE AF: 0.000542

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 09, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 29, 2022	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Gorlin syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 26, 2015

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 06, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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;