9-95456284-C-T

Variant names:

• chr9-95456284-C-T
• rs577110118
• NM_000264.5:c.3298G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM1 BP4_Moderate BP6 BS2

The NM_000264.5(PTCH1):​c.3298G>A​(p.Val1100Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,613,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. V1100F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 3.87
• Publications: 5 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: Likely_benign. The variant received -5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 18 uncertain in NM_000264.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.088645786).
• BP6: Variant 9-95456284-C-T is Benign according to our data. Variant chr9-95456284-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 409202.
• BS2: High AC in GnomAdExome4 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.3298G>A	p.Val1100Ile	missense	Exon 19 of 24	NP_000255.2	Q13635-1
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.3295G>A	p.Val1099Ile	missense	Exon 19 of 24	NP_001077072.1	Q13635-2
	PTCH1	NM_001354918.2		c.3142G>A	p.Val1048Ile	missense	Exon 18 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.3298G>A	p.Val1100Ile	missense	Exon 19 of 24	ENSP00000332353.6	Q13635-1
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.3295G>A	p.Val1099Ile	missense	Exon 19 of 24	ENSP00000389744.2	Q13635-2
	PTCH1	ENST00000429896.6	TSL:1	c.2845G>A	p.Val949Ile	missense	Exon 19 of 24	ENSP00000414823.2	Q13635-4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251036 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461512 Hom.: 0 Cov.: 33 AF XY: 0.0000151 AC XY: 11 AN XY: 727068

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53044

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74482

African (AFR) AF: 0.00 AC: 0 AN: 41568

American (AMR) AF: 0.0000653 AC: 1 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

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

Alfa AF: 0.000102 Hom.: 0

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	-	1	Gorlin syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Benign	0.86
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.12	N
PhyloP100		3.9
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.070	N
REVEL	Uncertain	0.33
Sift	Benign	0.76	T
Sift4G	Benign	0.79	T
Polyphen		0.030	B
Vest4		0.39
MutPred		0.42		Gain of catalytic residue at L1105 (P = 0.0748)
MVP		0.28
MPC		0.46
ClinPred		0.25	T
GERP RS		5.5
Varity_R		0.15
gMVP		0.57
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: rs577110118; hg19: chr9-98218566; COSMIC: COSV59485304; COSMIC: COSV59485304;