9-95508249-C-T

Variant names:

• chr9-95508249-C-T
• rs143494325
• NM_000264.5:c.113G>A

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.113G>A​(p.Gly38Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,603,018 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. G38R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 0.893
• Publications: 10 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=0.23521855).
• BP6: Variant 9-95508249-C-T is Benign according to our data. Variant chr9-95508249-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 216367.
• BS2: High AC in GnomAd4 at 17 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.113G>A	p.Gly38Glu	missense	Exon 1 of 24	NP_000255.2	Q13635-1
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.199-1650G>A		intron	N/A	NP_001077072.1	Q13635-2
	PTCH1	NM_001354918.2		c.113G>A	p.Gly38Glu	missense	Exon 1 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.113G>A	p.Gly38Glu	missense	Exon 1 of 24	ENSP00000332353.6	Q13635-1
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.199-1650G>A		intron	N/A	ENSP00000389744.2	Q13635-2
	PTCH1	ENST00000468211.6	TSL:1	c.4-1650G>A		intron	N/A	ENSP00000449745.1	A0A0C4DGJ5

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 151730 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000961

GnomAD2 exomes AF: 0.0000917 AC: 21 AN: 228974 AF XY: 0.000103

Gnomad AFR exome AF: 0.0000738

Gnomad AMR exome AF: 0.0000600

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000587

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000147

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000126 AC: 183 AN: 1451288 Hom.: 0 Cov.: 34 AF XY: 0.000137 AC XY: 99 AN XY: 721554

African (AFR) AF: 0.0000603 AC: 2 AN: 33164

American (AMR) AF: 0.0000452 AC: 2 AN: 44260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25978

East Asian (EAS) AF: 0.0000764 AC: 3 AN: 39254

South Asian (SAS) AF: 0.000117 AC: 10 AN: 85542

European-Finnish (FIN) AF: 0.0000403 AC: 2 AN: 49672

Middle Eastern (MID) AF: 0.00104 AC: 5 AN: 4818

European-Non Finnish (NFE) AF: 0.000141 AC: 156 AN: 1108808

Other (OTH) AF: 0.0000502 AC: 3 AN: 59792

GnomAD4 genome AF: 0.000112 AC: 17 AN: 151730 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74090

African (AFR) AF: 0.0000483 AC: 2 AN: 41408

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5170

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

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: 0.000162 AC: 11 AN: 67772

Other (OTH) AF: 0.000961 AC: 2 AN: 2082

Alfa AF: 0.0000367 Hom.: 0

Bravo AF: 0.000110

ExAC AF: 0.000126 AC: 15

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	1	-	Craniopharyngioma (1)
-	-	1	Gorlin syndrome (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Benign	0.91
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.65	T
M_CAP	Pathogenic	0.85	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.89
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	0.44	N
REVEL	Benign	0.16
Sift	Benign	0.38	T
Sift4G	Benign	0.19	T
Polyphen		0.0010	B
Vest4		0.18
MutPred		0.23		Loss of loop (P = 0.0073)
MVP		0.19
MPC		1.6
ClinPred		0.035	T
GERP RS		3.7
PromoterAI		0.0088	Neutral
Varity_R		0.043
gMVP		0.31
Mutation Taster		=34/66	disease causing

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: rs143494325; hg19: chr9-98270531; COSMIC: COSV59494982;