chr9-95449239-C-T

Variant names:

• chr9-95449239-C-T
• rs559827048
• NM_000264.5:c.3634G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000264.5(PTCH1):​c.3634G>A​(p.Gly1212Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,584,884 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1212D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (2 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.22
• 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, Orphanet, Labcorp Genetics (formerly Invitae)
• holoprosencephaly

  Inheritance: AD Classification: LIMITED Submitted by: Illumina

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0063804686).
• BP6: Variant 9-95449239-C-T is Benign according to our data. Variant chr9-95449239-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000722 (11/152324) while in subpopulation SAS AF = 0.00145 (7/4826). AF 95% confidence interval is 0.00068. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 11 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.3634G>A	p.Gly1212Ser	missense	Exon 22 of 24	NP_000255.2	Q13635-1
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.3631G>A	p.Gly1211Ser	missense	Exon 22 of 24	NP_001077072.1	Q13635-2
	PTCH1	NM_001354918.2		c.3478G>A	p.Gly1160Ser	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.3634G>A	p.Gly1212Ser	missense	Exon 22 of 24	ENSP00000332353.6	Q13635-1
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.3631G>A	p.Gly1211Ser	missense	Exon 22 of 24	ENSP00000389744.2	Q13635-2
	PTCH1	ENST00000429896.6	TSL:1	c.3181G>A	p.Gly1061Ser	missense	Exon 22 of 24	ENSP00000414823.2	Q13635-4

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000234 AC: 46 AN: 196296 AF XY: 0.000314

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000144

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000236

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000126 AC: 180 AN: 1432560 Hom.: 2 Cov.: 31 AF XY: 0.000159 AC XY: 113 AN XY: 709944

African (AFR) AF: 0.00 AC: 0 AN: 33046

American (AMR) AF: 0.000128 AC: 5 AN: 39156

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25462

East Asian (EAS) AF: 0.000130 AC: 5 AN: 38468

South Asian (SAS) AF: 0.00142 AC: 117 AN: 82628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51312

Middle Eastern (MID) AF: 0.000523 AC: 3 AN: 5734

European-Non Finnish (NFE) AF: 0.0000419 AC: 46 AN: 1097392

Other (OTH) AF: 0.0000674 AC: 4 AN: 59362

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74490

African (AFR) AF: 0.00 AC: 0 AN: 41578

American (AMR) AF: 0.000131 AC: 2 AN: 15306

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000388 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.000224 AC: 27

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Gorlin syndrome (2)
-	-	2	not provided (2)
-	-	1	Basal cell nevus syndrome 1 (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	PTCH1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.065
DANN	Benign	0.45
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.035	N
PhyloP100		-1.2
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.28	N
REVEL	Benign	0.18
Sift	Benign	0.58	T
Sift4G	Benign	0.81	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.42
MPC		0.076
ClinPred		0.0076	T
GERP RS		-7.8
Varity_R		0.026
gMVP		0.34
Mutation Taster		=83/17	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: rs559827048; hg19: chr9-98211521; COSMIC: COSV59474051;