9-95467118-T-G

Position:

• chr9-95467118-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_000264.5(PTCH1):​c.2558A>C​(p.Gln853Pro) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTCH1 NM_000264.5 missense, splice_region
• Scores: Splicing: ADA: 0.007144
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.83

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]

LOC100507346 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a topological_domain Extracellular (size 257) in uniprot entity PTC1_HUMAN there are 24 pathogenic changes around while only 5 benign (83%) in NM_000264.5
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.2558A>C	p.Gln853Pro	missense_variant, splice_region_variant	15/24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.2555A>C	p.Gln852Pro	missense_variant, splice_region_variant	15/24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.2558A>C	p.Gln853Pro	missense_variant, splice_region_variant	15/24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.2555A>C	p.Gln852Pro	missense_variant, splice_region_variant	15/24	5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gorlin syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 01, 2023

This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 853 of the PTCH1 protein (p.Gln853Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of nevoid basal cell carcinoma syndrome (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 428818). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 22, 2015

The p.Q853P variant (also known as c.2558A>C), located in coding exon 15 of the PTCH1 gene, results from an A to C substitution at nucleotide position 2558. The glutamine at codon 853 is replaced by proline, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.65% (greater than 150 alleles tested) in our clinical cohort. Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.Q853P remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.55	D;.;.;.;.;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;.;D;D;.;.;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.075	T
MutationAssessor	Uncertain	2.4	M;.;.;.;.;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.2	N;D;D;N;N;D;N
REVEL	Pathogenic	0.69
Sift	Benign	0.26	T;T;T;T;T;T;T
Sift4G	Benign	0.12	T;T;T;T;T;T;T
Polyphen		0.83	P;.;.;P;P;.;P
Vest4		0.81
MutPred		0.51		Loss of helix (P = 0.0196);.;.;.;.;.;.;
MVP		0.89
MPC		1.3
ClinPred		0.93	D
GERP RS		5.5
Varity_R		0.82
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0071
dbscSNV1_RF	Benign	0.092
SpliceAI score (max)		0.010		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: rs587778628; hg19: chr9-98229400;