rs143494325

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr9-95508249-C-A
• chr9-95508249-C-G
• chr9-95508249-C-T

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>T​(p.Gly38Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000336 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. 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 0.00040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:12
• 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=0.18916169).
• BP6: Variant 9-95508249-C-A is Benign according to our data. Variant chr9-95508249-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 188272.
• BS2: High AC in GnomAd4 at 60 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>T	p.Gly38Val	missense	Exon 1 of 24	NP_000255.2	Q13635-1
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.199-1650G>T		intron	N/A	NP_001077072.1	Q13635-2
	PTCH1	NM_001354918.2		c.113G>T	p.Gly38Val	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>T	p.Gly38Val	missense	Exon 1 of 24	ENSP00000332353.6	Q13635-1
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.199-1650G>T		intron	N/A	ENSP00000389744.2	Q13635-2
	PTCH1	ENST00000468211.6	TSL:1	c.4-1650G>T		intron	N/A	ENSP00000449745.1	A0A0C4DGJ5

Frequencies

GnomAD3 genomes AF: 0.000395 AC: 60 AN: 151730 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000475

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000487

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000301 AC: 69 AN: 228974 AF XY: 0.000292

Gnomad AFR exome AF: 0.000221

Gnomad AMR exome AF: 0.000150

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000280

Gnomad NFE exome AF: 0.000528

Gnomad OTH exome AF: 0.000177

GnomAD4 exome AF: 0.000330 AC: 479 AN: 1451288 Hom.: 0 Cov.: 34 AF XY: 0.000316 AC XY: 228 AN XY: 721554

African (AFR) AF: 0.000241 AC: 8 AN: 33164

American (AMR) AF: 0.000113 AC: 5 AN: 44260

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 25978

East Asian (EAS) AF: 0.00 AC: 0 AN: 39254

South Asian (SAS) AF: 0.0000585 AC: 5 AN: 85542

European-Finnish (FIN) AF: 0.000141 AC: 7 AN: 49672

Middle Eastern (MID) AF: 0.000415 AC: 2 AN: 4818

European-Non Finnish (NFE) AF: 0.000387 AC: 429 AN: 1108808

Other (OTH) AF: 0.000334 AC: 20 AN: 59792

GnomAD4 genome AF: 0.000395 AC: 60 AN: 151730 Hom.: 0 Cov.: 32 AF XY: 0.000337 AC XY: 25 AN XY: 74090

African (AFR) AF: 0.000314 AC: 13 AN: 41408

American (AMR) AF: 0.000590 AC: 9 AN: 15260

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

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

European-Finnish (FIN) AF: 0.000475 AC: 5 AN: 10518

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

European-Non Finnish (NFE) AF: 0.000487 AC: 33 AN: 67772

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.000440 Hom.: 0

Bravo AF: 0.000370

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000467 AC: 4

ExAC AF: 0.000319 AC: 38

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	not provided (6)
-	-	2	Gorlin syndrome (2)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	1	1	not specified (2)
-	-	1	Holoprosencephaly 7 (1)
-	-	1	PTCH1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.86	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	-0.027	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.89
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.21
Sift	Benign	0.19	T
Sift4G	Uncertain	0.037	D
Polyphen		0.099	B
Vest4		0.11
MVP		0.33
MPC		1.6
ClinPred		0.031	T
GERP RS		3.7
PromoterAI		-0.027	Neutral
Varity_R		0.071
gMVP		0.42
Mutation Taster		=41/59	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;