9-95508325-G-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000264.5(PTCH1):​c.37C>G​(p.Arg13Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000671 in 1,329,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. R13C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (0 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:6
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.050979435).
• BP6: Variant 9-95508325-G-C is Benign according to our data. Variant chr9-95508325-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 188208.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000637 (96/150606) while in subpopulation AMR AF = 0.00132 (20/15168). AF 95% confidence interval is 0.000873. There are 0 homozygotes in GnomAd4. There are 48 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 96 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH1	NM_000264.5	MANE Select	c.37C>G	p.Arg13Gly	missense	Exon 1 of 24	NP_000255.2
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.199-1726C>G		intron	N/A	NP_001077072.1
	PTCH1	NM_001354918.2		c.37C>G	p.Arg13Gly	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>G	p.Arg13Gly	missense	Exon 1 of 24	ENSP00000332353.6
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.199-1726C>G		intron	N/A	ENSP00000389744.2
	PTCH1	ENST00000468211.6	TSL:1	c.4-1726C>G		intron	N/A	ENSP00000449745.1

Frequencies

GnomAD3 genomes AF: 0.000638 AC: 96 AN: 150494 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000786

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000934

Gnomad OTH AF: 0.00145

GnomAD2 exomes AF: 0.000785 AC: 7 AN: 8920 AF XY: 0.000968

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00146

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000676 AC: 797 AN: 1179380 Hom.: 0 Cov.: 33 AF XY: 0.000714 AC XY: 408 AN XY: 571782

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

American (AMR) AF: 0.000876 AC: 8 AN: 9134

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

East Asian (EAS) AF: 0.00164 AC: 44 AN: 26852

South Asian (SAS) AF: 0.000173 AC: 8 AN: 46246

European-Finnish (FIN) AF: 0.0000637 AC: 2 AN: 31380

Middle Eastern (MID) AF: 0.000308 AC: 1 AN: 3248

European-Non Finnish (NFE) AF: 0.000730 AC: 712 AN: 975964

Other (OTH) AF: 0.000459 AC: 22 AN: 47894

GnomAD4 genome AF: 0.000637 AC: 96 AN: 150606 Hom.: 0 Cov.: 32 AF XY: 0.000652 AC XY: 48 AN XY: 73574

African (AFR) AF: 0.000146 AC: 6 AN: 41202

American (AMR) AF: 0.00132 AC: 20 AN: 15168

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.000788 AC: 4 AN: 5078

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.000934 AC: 63 AN: 67448

Other (OTH) AF: 0.00144 AC: 3 AN: 2086

Alfa AF: 0.0000694 Hom.: 0

Bravo AF: 0.000812

ExAC AF: 0.0000735 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
-	1	1	Gorlin syndrome (2)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	1	-	Gorlin syndrome;C1835820:Holoprosencephaly 7;C2751544:Basal cell carcinoma, susceptibility to, 1 (1)
-	1	-	Holoprosencephaly 7 (1)
-	1	-	not specified (1)
-	-	1	PTCH1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Benign	0.83
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.45	T
M_CAP	Pathogenic	0.86	D
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-1.3
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.26
Sift	Benign	0.65	T
Sift4G	Benign	0.48	T
Polyphen		0.0	B
Vest4		0.067
MutPred		0.21		Gain of relative solvent accessibility (P = 0.0166)
MVP		0.29
MPC		0.70
ClinPred		0.029	T
GERP RS		1.4
PromoterAI		0.0068	Neutral
Varity_R		0.14
gMVP		0.26
Mutation Taster		=80/20	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; COSMIC: COSV107393198;