rs761688859

Positions:

• chr9-95447323-C-A
• chr9-95447323-C-G
• chr9-95447323-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000264.5(PTCH1):​c.3933G>T​(p.Leu1311Phe) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0380

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.037150115).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.3933G>T	p.Leu1311Phe	missense_variant	23/24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.3930G>T	p.Leu1310Phe	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.3933G>T	p.Leu1311Phe	missense_variant	23/24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.3930G>T	p.Leu1310Phe	missense_variant	23/24	5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000406 AC: 1 AN: 246464 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134624

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000902

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000828 AC: 1

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

Mar 16, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PTCH1-related disease. This variant is present in population databases (rs761688859, ExAC 0.002%). This sequence change replaces leucine with phenylalanine at codon 1311 of the PTCH1 protein (p.Leu1311Phe). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and phenylalanine. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2023

The p.L1311F variant (also known as c.3933G>T), located in coding exon 23 of the PTCH1 gene, results from a G to T substitution at nucleotide position 3933. The leucine at codon 1311 is replaced by phenylalanine, an amino acid with highly 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	9.2
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;.;.;.;.;.;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.79	T;.;T;T;.;.;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.037	T;T;T;T;T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.6	L;.;.;.;.;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.54	N;N;N;N;N;N;N
REVEL	Benign	0.21
Sift	Benign	0.65	T;T;T;T;T;T;T
Sift4G	Benign	0.71	T;T;T;T;T;T;T
Polyphen		0.019	B;.;.;B;B;.;B
Vest4		0.15
MutPred		0.20		Loss of catalytic residue at L1311 (P = 0.0077);.;.;.;.;.;.;
MVP		0.27
MPC		0.083
ClinPred		0.18	T
GERP RS		2.7
Varity_R		0.061
gMVP		0.23

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: rs761688859; hg19: chr9-98209605;