rs62637630

chr9-95449306-G-Achr9-95449306-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000264.5(PTCH1):c.3567C>T(p.Gly1189=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,552,730 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00060 (7 hom.)
• Consequence: PTCH1 NM_000264.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.295

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 9-95449306-G-A is Benign according to our data. Variant chr9-95449306-G-A is described in ClinVar as [Benign]. Clinvar id is 220553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95449306-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.295 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00606 (923/152384) while in subpopulation AFR AF= 0.0213 (887/41592). AF 95% confidence interval is 0.0202. There are 7 homozygotes in gnomad4. There are 427 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 922 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH1	NM_000264.5	c.3567C>T	p.Gly1189=	synonymous_variant	22/24	ENST00000331920.11
PTCH1	NM_001083603.3	c.3564C>T	p.Gly1188=	synonymous_variant	22/24	ENST00000437951.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11	c.3567C>T	p.Gly1189=	synonymous_variant	22/24	5	NM_000264.5	A2
PTCH1	ENST00000437951.6	c.3564C>T	p.Gly1188=	synonymous_variant	22/24	5	NM_001083603.3

Frequencies

GnomAD3 genomes AF: 0.00606 AC: 922 AN: 152266 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00149 AC: 234 AN: 157404 Hom.: 3 AF XY: 0.00109 AC XY: 91 AN XY: 83460

Gnomad AFR exome AF: 0.0215

Gnomad AMR exome AF: 0.000924

Gnomad ASJ exome AF: 0.000117

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000215

Gnomad FIN exome AF: 0.000401

Gnomad NFE exome AF: 0.0000793

Gnomad OTH exome AF: 0.000678

GnomAD4 exome AF: 0.000604 AC: 846 AN: 1400346 Hom.: 7 Cov.: 31 AF XY: 0.000538 AC XY: 372 AN XY: 691324

Gnomad4 AFR exome AF: 0.0202

Gnomad4 AMR exome AF: 0.000836

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000113

Gnomad4 FIN exome AF: 0.000197

Gnomad4 NFE exome AF: 0.0000629

Gnomad4 OTH exome AF: 0.00122

GnomAD4 genome AF: 0.00606 AC: 923 AN: 152384 Hom.: 7 Cov.: 33 AF XY: 0.00573 AC XY: 427 AN XY: 74514

Gnomad4 AFR AF: 0.0213

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00185 Hom.: 0

Bravo AF: 0.00622

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 07, 2021	- -
Benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 02, 2022	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Gorlin syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2017

This alteration is classified as 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. -

Gorlin syndrome;C1835820:Holoprosencephaly 7;C2751544:Basal cell carcinoma, susceptibility to, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 27, 2022

- -

Holoprosencephaly 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	4.8
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs62637630; hg19: chr9-98211588;