rs970679518

Positions:

• chr9-95449089-G-A
• chr9-95449089-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP6

The NM_000264.5(PTCH1):​c.3784C>T​(p.Pro1262Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. P1262L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.58

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 2 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.
• BP6: Variant 9-95449089-G-A is Benign according to our data. Variant chr9-95449089-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 453865.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.3784C>T	p.Pro1262Ser	missense_variant	22/24	ENST00000331920.11
PTCH1	NM_001083603.3	c.3781C>T	p.Pro1261Ser	missense_variant	22/24	ENST00000437951.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11	c.3784C>T	p.Pro1262Ser	missense_variant	22/24	5	NM_000264.5	A2
PTCH1	ENST00000437951.6	c.3781C>T	p.Pro1261Ser	missense_variant	22/24	5	NM_001083603.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000378

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

Aug 16, 2023

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: 453865). 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. 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. This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1262 of the PTCH1 protein (p.Pro1262Ser). -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 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	0.14
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;.;.;.;.;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D;.;D;D;.;.;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Benign	1.9	L;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N;N
REVEL	Uncertain	0.59
Sift	Benign	0.10	T;T;T;T;T;T;T
Sift4G	Benign	0.28	T;T;T;T;T;T;T
Polyphen		1.0	D;.;.;D;D;.;D
Vest4		0.60
MVP		0.82
MPC		0.089
ClinPred		0.95	D
GERP RS		5.5
Varity_R		0.098
gMVP		0.45

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

Publications

LitVar

Other links and lift over

dbSNP: rs970679518; hg19: chr9-98211371;