chr9-95485685-C-T

Variant names:

• chr9-95485685-C-T
• rs1554702009
• NM_000264.5:c.584G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP3 PP5_Moderate

The NM_000264.5(PTCH1):​c.584G>A​(p.Arg195Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R195T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTCH1 NM_000264.5 missense, splice_region
• Scores: Splicing: ADA: 0.9789
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.15
• Publications: 0 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-95485685-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 453903.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 9-95485685-C-T is Pathogenic according to our data. Variant chr9-95485685-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1076491.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.584G>A	p.Arg195Lys	missense_variant, splice_region_variant	Exon 3 of 24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.581G>A	p.Arg194Lys	missense_variant, splice_region_variant	Exon 3 of 24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.584G>A	p.Arg195Lys	missense_variant, splice_region_variant	Exon 3 of 24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.581G>A	p.Arg194Lys	missense_variant, splice_region_variant	Exon 3 of 24	5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Gorlin syndrome Pathogenic:1

Sep 09, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 16203740, 27561271). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with nevoid basal cell carcinoma syndrome (NBCCS) (PMID: 16203740, 22434048, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with lysine at codon 195 of the PTCH1 protein (p.Arg195Lys). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and lysine. This variant also falls at the last nucleotide of exon 3 of the PTCH1 coding sequence, which is part of the consensus splice site for this exon. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	34
DANN	Benign	0.86
DEOGEN2	Benign	0.18	T;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D;.;D;D;.;.;D;.;.;.;D;D;D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.090	N;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		3.2
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	0.68	N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.32
Sift	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;.;.;B;B;.;B;.;.;.;.;.;.
Vest4		0.30
MutPred		0.37		Gain of methylation at R195 (P = 0.0219);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.40
MPC		0.55
ClinPred		0.79	D
GERP RS		5.9
Varity_R		0.59
gMVP		0.69
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.94		Position offset: -37
DS_DL_spliceai		0.69		Position offset: 0

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

Other links and lift over

dbSNP: rs1554702009; hg19: chr9-98247967; COSMIC: COSV59500261; COSMIC: COSV59500261;