rs2236405

chr9-95449290-T-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000264.5(PTCH1):c.3583A>T(p.Thr1195Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0223 in 1,557,458 control chromosomes in the GnomAD database, including 1,174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1195I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.047 (348 hom., cov: 33)
  • Exomes 𝑓: 0.020 (826 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14 O:1
• Conservation: PhyloP100: 4.02

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 -17 ACMG points.

• PM1: In a modified_residue Phosphothreonine (size 0) in uniprot entity PTC1_HUMAN
• PP2: Missense variant where missense usually causes diseases, PTCH1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0019354224).
• BP6: Variant 9-95449290-T-A is Benign according to our data. Variant chr9-95449290-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 135100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95449290-T-A is described in Lovd as [Benign]. Variant chr9-95449290-T-A is described in Lovd as [Pathogenic].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH1	NM_000264.5	c.3583A>T	p.Thr1195Ser	missense_variant	22/24	ENST00000331920.11
PTCH1	NM_001083603.3	c.3580A>T	p.Thr1194Ser	missense_variant	22/24	ENST00000437951.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11	c.3583A>T	p.Thr1195Ser	missense_variant	22/24	5	NM_000264.5	A2
PTCH1	ENST00000437951.6	c.3580A>T	p.Thr1194Ser	missense_variant	22/24	5	NM_001083603.3

Frequencies

GnomAD3 genomes AF: 0.0469 AC: 7130 AN: 152148 Hom.: 347 Cov.: 33

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0214

Gnomad ASJ AF: 0.0415

Gnomad EAS AF: 0.134

Gnomad SAS AF: 0.0532

Gnomad FIN AF: 0.00668

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.0325

GnomAD3 exomes AF: 0.0340 AC: 5516 AN: 162192 Hom.: 228 AF XY: 0.0339 AC XY: 2919 AN XY: 85986

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.0128

Gnomad ASJ exome AF: 0.0425

Gnomad EAS exome AF: 0.132

Gnomad SAS exome AF: 0.0481

Gnomad FIN exome AF: 0.00844

Gnomad NFE exome AF: 0.0125

Gnomad OTH exome AF: 0.0254

GnomAD4 exome AF: 0.0197 AC: 27632 AN: 1405192 Hom.: 826 Cov.: 31 AF XY: 0.0202 AC XY: 14008 AN XY: 693950

Gnomad4 AFR exome AF: 0.122

Gnomad4 AMR exome AF: 0.0137

Gnomad4 ASJ exome AF: 0.0441

Gnomad4 EAS exome AF: 0.127

Gnomad4 SAS exome AF: 0.0472

Gnomad4 FIN exome AF: 0.00728

Gnomad4 NFE exome AF: 0.0106

Gnomad4 OTH exome AF: 0.0287

GnomAD4 genome AF: 0.0469 AC: 7148 AN: 152266 Hom.: 348 Cov.: 33 AF XY: 0.0478 AC XY: 3558 AN XY: 74478

Gnomad4 AFR AF: 0.116

Gnomad4 AMR AF: 0.0213

Gnomad4 ASJ AF: 0.0415

Gnomad4 EAS AF: 0.134

Gnomad4 SAS AF: 0.0539

Gnomad4 FIN AF: 0.00668

Gnomad4 NFE AF: 0.0113

Gnomad4 OTH AF: 0.0321

Alfa AF: 0.0218 Hom.: 67

Bravo AF: 0.0509

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.0153 AC: 59

ESP6500AA AF: 0.0976 AC: 426

ESP6500EA AF: 0.0131 AC: 111

ExAC AF: 0.0243 AC: 2734

Asia WGS AF: 0.0810 AC: 281 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4 Other:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 13, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 02, 2016	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 27, 2013	The variant is found in PTCH panel(s). -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 24, 2016	Variant summary: The PTCH1 c.3583A>T (p.Thr1195Ser) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1271/23496 control chromosomes (51 homozygotes) at a frequency of 0.0540943, which is approximately 3157 times the estimated maximal expected allele frequency of a pathogenic PTCH1 variant (0.0000171), suggesting this variant is likely a benign polymorphism. This variant has been reported in NBCCS patients. One patient also carried a potentially pathogenic variant c.3499G>A (p.G1167R), further supporting the benign classification. In addition, multiple clinical diagnostic laboratories classified this variant as benign. Taken together, this variant is classified as benign. -

Gorlin syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 09, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 03, 2014	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. -

Holoprosencephaly 7 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.52	D;.;.;.;.;.;.
Eigen	Benign	0.043
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	D;.;D;D;.;.;D
MetaRNN	Benign	0.0019	T;T;T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.3	M;.;.;.;.;.;.
MutationTaster	Benign	0.000046	P;P;P;P;P;P;P
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.086	T;T;T;T;T;T;T
Sift4G	Benign	0.24	T;T;T;T;T;T;T
Polyphen		0.47	P;.;.;B;B;.;P
Vest4		0.25
MPC		0.60
ClinPred		0.016	T
GERP RS		4.6
Varity_R		0.15
gMVP		0.56

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: rs2236405; hg19: chr9-98211572; COSMIC: COSV59467963;