chr9-95508283-G-C

Variant names:

• chr9-95508283-G-C
• rs1245076183
• NM_000264.5:c.79C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000264.5(PTCH1):​c.79C>G​(p.Pro27Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P27S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.646
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2239429).

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.79C>G	p.Pro27Ala	missense	Exon 1 of 24	NP_000255.2
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.199-1684C>G		intron	N/A	NP_001077072.1
	PTCH1	NM_001354918.2		c.79C>G	p.Pro27Ala	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.79C>G	p.Pro27Ala	missense	Exon 1 of 24	ENSP00000332353.6
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.199-1684C>G		intron	N/A	ENSP00000389744.2
	PTCH1	ENST00000468211.6	TSL:1	c.4-1684C>G		intron	N/A	ENSP00000449745.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.16e-7 AC: 1 AN: 1396116 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 690254

African (AFR) AF: 0.0000326 AC: 1 AN: 30700

American (AMR) AF: 0.00 AC: 0 AN: 37624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24552

East Asian (EAS) AF: 0.00 AC: 0 AN: 35812

South Asian (SAS) AF: 0.00 AC: 0 AN: 79498

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43716

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4174

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1082442

Other (OTH) AF: 0.00 AC: 0 AN: 57598

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Gorlin syndrome Uncertain:1

May 13, 2014

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change has not been reported in affected patients, and has not been reported as a common polymorphism in the population. Indirect and predictive evidence suggest that this sequence change does not affect protein function, but these predictions have not been confirmed by functional studies. This substitution affects a poorly conserved amino acid. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, MutationTaster, AlignGVGD) suggest that this sequence change is likely to be tolerated, but these predictions have not been confirmed by functional studies.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.40	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.65
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.81	N
REVEL	Benign	0.17
Sift	Benign	0.17	T
Sift4G	Uncertain	0.026	D
Polyphen		0.0030	B
Vest4		0.19
MutPred		0.22		Loss of relative solvent accessibility (P = 0.0071)
MVP		0.58
MPC		0.53
ClinPred		0.11	T
GERP RS		1.5
PromoterAI		-0.019	Neutral
Varity_R		0.034
gMVP		0.44
Mutation Taster		=92/8	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: rs1245076183; hg19: chr9-98270565;