rs1085307511

Variant names:

• chr9-95477547-C-A
• rs1085307511
• NM_000264.5:c.1503G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-95477547-C-A
• chr9-95477547-C-G
• chr9-95477547-C-T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM1 PM2 PM5 PP3_Strong PP5

The NM_000264.5(PTCH1):​c.1503G>T​(p.Gln501His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002099648: Targeted RNA studies using blood from this patient demonstrate that this variant alters RNA splicing, leading to an aberrant splice product, which results in the in-frame skipping of exon 10 and is predicted to result in an in-frame deletion of 52 amino acids. Both wildtype and variant RNA transcripts were observed in the proband" and additional evidence is available in ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q501R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTCH1 NM_000264.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.39
• 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, Orphanet, Labcorp Genetics (formerly Invitae)
• holoprosencephaly

  Inheritance: AD Classification: LIMITED Submitted by: Illumina

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002099648: Targeted RNA studies using blood from this patient demonstrate that this variant alters RNA splicing, leading to an aberrant splice product, which results in the in-frame skipping of exon 10 and is predicted to result in an in-frame deletion of 52 amino acids. Both wildtype and variant RNA transcripts were observed in the proband; however, the aberrant splice product was expressed at higher levels compared to wildtype. The aberrant splice product was detected at low levels in the maternal sample and control samples. These studies cannot exclude the possibility that this variant may have a different impact on alternative splicing and expression in other tissues.; This variant is associated with the following publications: (PMID: 11369205)
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 21 uncertain in NM_000264.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-95477548-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 217294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 9-95477547-C-A is Pathogenic according to our data. Variant chr9-95477547-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1342766.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000264.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH1	NM_000264.5	MANE Select	c.1503G>T	p.Gln501His	missense splice_region	Exon 10 of 24	NP_000255.2	Q13635-1
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.1500G>T	p.Gln500His	missense splice_region	Exon 10 of 24	NP_001077072.1	Q13635-2
	PTCH1	NM_001083602.3		c.1305G>T	p.Gln435His	missense splice_region	Exon 10 of 24	NP_001077071.1	Q13635-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH1	ENST00000331920.11	TSL:5 MANE Select	c.1503G>T	p.Gln501His	missense splice_region	Exon 10 of 24	ENSP00000332353.6	Q13635-1
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.1500G>T	p.Gln500His	missense splice_region	Exon 10 of 24	ENSP00000389744.2	Q13635-2
	PTCH1	ENST00000429896.6	TSL:1	c.1050G>T	p.Gln350His	missense splice_region	Exon 10 of 24	ENSP00000414823.2	Q13635-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Gorlin syndrome (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.4
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.88
MutPred		0.56		Gain of glycosylation at T499 (P = 0.0514)
MVP		0.95
MPC		1.4
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.89
gMVP		0.92
Mutation Taster		=3/97	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.66		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.66		Position offset: 0

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

Other links and lift over

dbSNP: rs1085307511; hg19: chr9-98239829;