rs773298544

Positions:

• chr9-95447210-G-A
• chr9-95447210-G-C
• chr9-95447210-G-T

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.4046C>T​(p.Pro1349Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 4.18

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=0.102380574).
• BP6: Variant 9-95447210-G-A is Benign according to our data. Variant chr9-95447210-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 409204.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.4046C>T	p.Pro1349Leu	missense_variant	23/24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.4043C>T	p.Pro1348Leu	missense_variant	23/24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.4046C>T	p.Pro1349Leu	missense_variant	23/24	5	NM_000264.5	ENSP00000332353	A2
PTCH1	ENST00000437951.6	c.4043C>T	p.Pro1348Leu	missense_variant	23/24	5	NM_001083603.3	ENSP00000389744

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000122 AC: 3 AN: 246634 Hom.: 0 AF XY: 0.00000744 AC XY: 1 AN XY: 134400

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.00000205 AC: 3 AN: 1460638 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726620

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

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: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000829 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Jan 18, 2023

To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000087 (3/34522 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2022

The p.P1349L variant (also known as c.4046C>T), located in coding exon 23 of the PTCH1 gene, results from a C to T substitution at nucleotide position 4046. The proline at codon 1349 is replaced by leucine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Gorlin syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T;.;.;.;.;.;.
Eigen	Benign	-0.18
Eigen_PC	Benign	0.028
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D;.;D;D;.;.;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.10	T;T;T;T;T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.8	L;.;.;.;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.67	N;N;N;N;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.26	T;T;T;T;T;T;T
Sift4G	Benign	0.66	T;T;T;T;T;T;T
Polyphen		0.0020	B;.;.;B;B;.;B
Vest4		0.32
MutPred		0.24		Gain of MoRF binding (P = 0.053);.;.;.;.;.;.;
MVP		0.59
MPC		0.078
ClinPred		0.37	T
GERP RS		5.1
Varity_R		0.064
gMVP		0.21

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: rs773298544; hg19: chr9-98209492;