rs786204147

Variant names:

• chr9-95508325-G-A
• rs779791579
• NM_000264.5:c.37C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-95508325-G-A
• chr9-95508325-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000264.5(PTCH1):​c.37C>T​(p.Arg13Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000339 in 1,179,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R13G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -1.28
• Publications: 7 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22267309).

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.37C>T	p.Arg13Cys	missense	Exon 1 of 24	NP_000255.2
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.199-1726C>T		intron	N/A	NP_001077072.1
	PTCH1	NM_001354918.2		c.37C>T	p.Arg13Cys	missense	Exon 1 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.37C>T	p.Arg13Cys	missense	Exon 1 of 24	ENSP00000332353.6
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.199-1726C>T		intron	N/A	ENSP00000389744.2
	PTCH1	ENST00000468211.6	TSL:1	c.4-1726C>T		intron	N/A	ENSP00000449745.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000339 AC: 4 AN: 1179392 Hom.: 0 Cov.: 33 AF XY: 0.00000175 AC XY: 1 AN XY: 571788

African (AFR) AF: 0.00 AC: 0 AN: 22972

American (AMR) AF: 0.000109 AC: 1 AN: 9134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15690

East Asian (EAS) AF: 0.00 AC: 0 AN: 26852

South Asian (SAS) AF: 0.00 AC: 0 AN: 46246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3248

European-Non Finnish (NFE) AF: 0.00000307 AC: 3 AN: 975976

Other (OTH) AF: 0.00 AC: 0 AN: 47894

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Basal cell carcinoma, susceptibility to, 1 (1)
-	1	-	Gorlin syndrome (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.0	N
PhyloP100		-1.3
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.23
Sift	Benign	0.066	T
Sift4G	Benign	0.20	T
Polyphen		0.35	B
Vest4		0.088
MutPred		0.22		Loss of MoRF binding (P = 0.078)
MVP		0.45
MPC		0.74
ClinPred		0.16	T
GERP RS		1.4
PromoterAI		0.0099	Neutral
Varity_R		0.11
gMVP		0.32
Mutation Taster		=85/15	polymorphism

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: rs779791579; hg19: chr9-98270607;