rs147067171

Variant names:

• chr9-95447309-T-C
• rs147067171
• NM_000264.5:c.3947A>G
• PTCH1 p.Tyr1316Cys

Your query was ambiguous. Multiple possible variants found:

• chr9-95447309-T-C
• chr9-95447309-T-A
• chr9-95447309-T-G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 4P and 10B. PS3 BP4_Moderate BS1 BS2

The NM_000264.5(PTCH1):​c.3947A>G​(p.Tyr1316Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000744 in 1,609,922 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). ClinVar reports functional evidence for this variant: "SCV000259154: rare variant, functional studies demonstrating is deleterious effect on protein.". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1316H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00077 (0 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:9
• Conservation: PhyloP100: 3.94
• Publications: 17 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nevoid basal cell carcinoma syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, ClinGen
• holoprosencephaly

  Inheritance: AD Classification: LIMITED Submitted by: Illumina

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000259154: rare variant, functional studies demonstrating is deleterious effect on protein.
• BP4: Computational evidence support a benign effect (MetaRNN=0.111567646).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000475 (72/151594) while in subpopulation NFE AF = 0.000899 (61/67818). AF 95% confidence interval is 0.000718. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 72 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.3947A>G	p.Tyr1316Cys	missense	Exon 23 of 24	NP_000255.2	Q13635-1
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.3944A>G	p.Tyr1315Cys	missense	Exon 23 of 24	NP_001077072.1	Q13635-2
	PTCH1	NM_001354918.2		c.3791A>G	p.Tyr1264Cys	missense	Exon 22 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.3947A>G	p.Tyr1316Cys	missense	Exon 23 of 24	ENSP00000332353.6	Q13635-1
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.3944A>G	p.Tyr1315Cys	missense	Exon 23 of 24	ENSP00000389744.2	Q13635-2
	PTCH1	ENST00000429896.6	TSL:1	c.3494A>G	p.Tyr1165Cys	missense	Exon 23 of 24	ENSP00000414823.2	Q13635-4

Frequencies

GnomAD3 genomes AF: 0.000475 AC: 72 AN: 151594 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000899

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000548 AC: 135 AN: 246202 AF XY: 0.000565

Gnomad AFR exome AF: 0.000137

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.000905

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000940

Gnomad OTH exome AF: 0.000498

GnomAD4 exome AF: 0.000771 AC: 1125 AN: 1458328 Hom.: 0 Cov.: 31 AF XY: 0.000758 AC XY: 550 AN XY: 725572

African (AFR) AF: 0.000150 AC: 5 AN: 33372

American (AMR) AF: 0.000336 AC: 15 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.000999 AC: 26 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86236

European-Finnish (FIN) AF: 0.000248 AC: 13 AN: 52346

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5756

European-Non Finnish (NFE) AF: 0.000904 AC: 1003 AN: 1110076

Other (OTH) AF: 0.000764 AC: 46 AN: 60220

GnomAD4 genome AF: 0.000475 AC: 72 AN: 151594 Hom.: 0 Cov.: 32 AF XY: 0.000338 AC XY: 25 AN XY: 74026

African (AFR) AF: 0.0000242 AC: 1 AN: 41298

American (AMR) AF: 0.000328 AC: 5 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000899 AC: 61 AN: 67818

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000831 Hom.: 0

Bravo AF: 0.000495

EpiCase AF: 0.000981

EpiControl AF: 0.000652

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	Holoprosencephaly 7;C2751544:Basal cell carcinoma, susceptibility to, 1;CN376810:Basal cell nevus syndrome 1 (1)
-	1	-	not specified (1)
-	-	1	PTCH1-related disorder (1)
1	-	-	Rieger anomaly;C0344559:Irido-corneo-trabecular dysgenesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.040
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	0.62	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.9
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.65	N
REVEL	Uncertain	0.47
Sift	Benign	0.063	T
Sift4G	Benign	0.10	T
Varity_R		0.11
gMVP		0.54
Mutation Taster		=0/100	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs147067171;

hg19: chr9-98209591;