rs587776689

Variant names:

• chr9-95453587-T-A
• rs587776689
• NM_000264.5:c.3340A>T

Your query was ambiguous. Multiple possible variants found:

• chr9-95453587-T-A
• chr9-95453587-T-G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000264.5(PTCH1):​c.3340A>T​(p.Arg1114Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. R1114R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.88
• Publications: 6 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 9-95453587-T-A is Pathogenic according to our data. Variant chr9-95453587-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 8220.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH1	NM_000264.5	MANE Select	c.3340A>T	p.Arg1114Trp	missense	Exon 20 of 24	NP_000255.2
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.3337A>T	p.Arg1113Trp	missense	Exon 20 of 24	NP_001077072.1
	PTCH1	NM_001354918.2		c.3184A>T	p.Arg1062Trp	missense	Exon 19 of 23	NP_001341847.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH1	ENST00000331920.11	TSL:5 MANE Select	c.3340A>T	p.Arg1114Trp	missense	Exon 20 of 24	ENSP00000332353.6
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.3337A>T	p.Arg1113Trp	missense	Exon 20 of 24	ENSP00000389744.2
	PTCH1	ENST00000429896.6	TSL:1	c.2887A>T	p.Arg963Trp	missense	Exon 20 of 24	ENSP00000414823.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Basal cell carcinoma, somatic Pathogenic:1

Jun 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		3.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.94		Loss of helix (P = 0.0558)
MVP		0.98
MPC		1.5
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.90
gMVP		0.97
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587776689; hg19: chr9-98215869; COSMIC: COSV59503815;