rs560967532

Variant names:

• chr9-95449256-C-T
• rs560967532
• NM_000264.5:c.3617G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-95449256-C-T
• chr9-95449256-C-G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_000264.5(PTCH1):​c.3617G>A​(p.Arg1206His) variant causes a missense change. The variant allele was found at a frequency of 0.000122 in 1,569,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1206C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:8 O:1
• Conservation: PhyloP100: 4.57
• 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, Orphanet, Labcorp Genetics (formerly Invitae)
• holoprosencephaly

  Inheritance: AD Classification: LIMITED Submitted by: Illumina

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.097904354).
• BP6: Variant 9-95449256-C-T is Benign according to our data. Variant chr9-95449256-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 135101.
• BS2: High AC in GnomAd4 at 23 AD gene.

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.3617G>A	p.Arg1206His	missense	Exon 22 of 24	NP_000255.2	Q13635-1
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.3614G>A	p.Arg1205His	missense	Exon 22 of 24	NP_001077072.1	Q13635-2
	PTCH1	NM_001354918.2		c.3461G>A	p.Arg1154His	missense	Exon 21 of 23	NP_001341847.1	A0A1W5YLI7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH1	ENST00000331920.11	TSL:5 MANE Select	c.3617G>A	p.Arg1206His	missense	Exon 22 of 24	ENSP00000332353.6	Q13635-1
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.3614G>A	p.Arg1205His	missense	Exon 22 of 24	ENSP00000389744.2	Q13635-2
	PTCH1	ENST00000429896.6	TSL:1	c.3164G>A	p.Arg1055His	missense	Exon 22 of 24	ENSP00000414823.2	Q13635-4

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152248 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000114 AC: 20 AN: 175912 AF XY: 0.0000854

Gnomad AFR exome AF: 0.0000977

Gnomad AMR exome AF: 0.000386

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000110

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000119 AC: 168 AN: 1417380 Hom.: 0 Cov.: 31 AF XY: 0.000110 AC XY: 77 AN XY: 700822

African (AFR) AF: 0.0000612 AC: 2 AN: 32656

American (AMR) AF: 0.000324 AC: 12 AN: 37072

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25328

East Asian (EAS) AF: 0.0000798 AC: 3 AN: 37576

South Asian (SAS) AF: 0.0000740 AC: 6 AN: 81084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50012

Middle Eastern (MID) AF: 0.000524 AC: 3 AN: 5720

European-Non Finnish (NFE) AF: 0.000122 AC: 133 AN: 1089114

Other (OTH) AF: 0.000153 AC: 9 AN: 58818

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152366 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74504

African (AFR) AF: 0.0000721 AC: 3 AN: 41582

American (AMR) AF: 0.000261 AC: 4 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000153 Hom.: 0

Bravo AF: 0.000166

ExAC AF: 0.0000760 AC: 9

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	Gorlin syndrome (2)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Holoprosencephaly 7 (1)
-	-	1	not specified (2)
1	-	-	Polydactyly of a triphalangeal thumb (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.045
Eigen_PC	Benign	0.066
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.098	T
MetaSVM	Uncertain	0.095	D
MutationAssessor	Benign	1.5	L
PhyloP100		4.6
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.50	N
REVEL	Uncertain	0.42
Sift	Benign	0.12	T
Sift4G	Benign	0.42	T
Polyphen		0.066	B
Vest4		0.32
MVP		0.34
MPC		0.095
ClinPred		0.029	T
GERP RS		5.3
Varity_R		0.15
gMVP		0.46
Mutation Taster		=51/49	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: rs560967532; hg19: chr9-98211538;