rs761204245

Variant names:

• chr9-95508294-G-A
• rs761204245
• NM_000264.5:c.68C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-95508294-G-A
• chr9-95508294-G-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000264.5(PTCH1):​c.68C>T​(p.Ala23Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000877 in 1,368,828 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. A23T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000088 (0 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 2.50
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18707046).
• BS2: High AC in GnomAdExome4 at 12 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.68C>T	p.Ala23Val	missense	Exon 1 of 24	NP_000255.2
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.199-1695C>T		intron	N/A	NP_001077072.1
	PTCH1	NM_001354918.2		c.68C>T	p.Ala23Val	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.68C>T	p.Ala23Val	missense	Exon 1 of 24	ENSP00000332353.6
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.199-1695C>T		intron	N/A	ENSP00000389744.2
	PTCH1	ENST00000468211.6	TSL:1	c.4-1695C>T		intron	N/A	ENSP00000449745.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000163 AC: 2 AN: 122990 AF XY: 0.0000146

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000959

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000877 AC: 12 AN: 1368828 Hom.: 0 Cov.: 33 AF XY: 0.00000889 AC XY: 6 AN XY: 675048

African (AFR) AF: 0.00 AC: 0 AN: 29564

American (AMR) AF: 0.0000589 AC: 2 AN: 33956

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23416

East Asian (EAS) AF: 0.00 AC: 0 AN: 34200

South Asian (SAS) AF: 0.00 AC: 0 AN: 75822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41848

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4024

European-Non Finnish (NFE) AF: 0.00000842 AC: 9 AN: 1069452

Other (OTH) AF: 0.0000177 AC: 1 AN: 56546

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000101 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.53	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.5
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.27	N
REVEL	Benign	0.17
Sift	Benign	0.33	T
Sift4G	Benign	0.73	T
Polyphen		0.0070	B
Vest4		0.096
MutPred		0.22		Gain of sheet (P = 0.0344)
MVP		0.16
MPC		0.54
ClinPred		0.051	T
GERP RS		0.36
PromoterAI		-0.016	Neutral
Varity_R		0.078
gMVP		0.37
Mutation Taster		=77/23	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: rs761204245; hg19: chr9-98270576;