9-95458171-G-C

Position:

• chr9-95458171-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2 PP2 BP4_Moderate BP6

The NM_000264.5(PTCH1):​c.3010C>G​(p.Leu1004Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. L1004R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.83

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PTCH1. . Gene score misZ 1.6774 (greater than the threshold 3.09). Trascript score misZ 3.1343 (greater than threshold 3.09). GenCC has associacion of gene with holoprosencephaly 7, nevoid basal cell carcinoma syndrome, holoprosencephaly.
• BP4: Computational evidence support a benign effect (MetaRNN=0.21242073).
• BP6: Variant 9-95458171-G-C is Benign according to our data. Variant chr9-95458171-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 220652.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH1	NM_000264.5	c.3010C>G	p.Leu1004Val	missense_variant	18/24	ENST00000331920.11
PTCH1	NM_001083603.3	c.3007C>G	p.Leu1003Val	missense_variant	18/24	ENST00000437951.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11	c.3010C>G	p.Leu1004Val	missense_variant	18/24	5	NM_000264.5	A2
PTCH1	ENST00000437951.6	c.3007C>G	p.Leu1003Val	missense_variant	18/24	5	NM_001083603.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Gorlin syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2023

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1004 of the PTCH1 protein (p.Leu1004Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PTCH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 220652). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PTCH1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 08, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.00037	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.40	T;.;.;.;.;.;.
Eigen	Benign	-0.15
Eigen_PC	Benign	0.0021
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D;.;D;D;.;.;D
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	0.41	N;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.35	N;N;N;N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.53	T;T;T;T;T;T;T
Sift4G	Benign	0.11	T;T;T;T;T;T;T
Polyphen		0.41	B;.;.;B;B;.;B
Vest4		0.37
MutPred		0.64		Loss of solvent accessibility (P = 0.0533);.;.;.;.;.;.;
MVP		0.48
MPC		0.63
ClinPred		0.66	D
GERP RS		3.9
Varity_R		0.41
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs864622620; hg19: chr9-98220453;