rs779204091

chr9-95479146-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2 PP3

The NM_000264.5(PTCH1):c.1069G>A(p.Ala357Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A357V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: PTCH1 NM_000264.5 missense, splice_region
• Scores: Splicing: ADA: 0.9920
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.57

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.

• PP2: Missense variant where missense usually causes diseases, PTCH1
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH1	NM_000264.5	c.1069G>A	p.Ala357Thr	missense_variant, splice_region_variant	8/24	ENST00000331920.11
PTCH1	NM_001083603.3	c.1066G>A	p.Ala356Thr	missense_variant, splice_region_variant	8/24	ENST00000437951.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11	c.1069G>A	p.Ala357Thr	missense_variant, splice_region_variant	8/24	5	NM_000264.5	A2
PTCH1	ENST00000437951.6	c.1066G>A	p.Ala356Thr	missense_variant, splice_region_variant	8/24	5	NM_001083603.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251488 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135918

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: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727236

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000624 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 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

Invitae

Sep 29, 2023

This variant has not been reported in the literature in individuals affected with PTCH1-related conditions. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 357 of the PTCH1 protein (p.Ala357Thr). This variant is present in population databases (rs779204091, gnomAD 0.006%). ClinVar contains an entry for this variant (Variation ID: 571865). 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

Feb 16, 2024

The p.A357T variant (also known as c.1069G>A), located in coding exon 8 of the PTCH1 gene, results from a G to A substitution at nucleotide position 1069. The alanine at codon 357 is replaced by threonine, an amino acid with similar properties. 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 this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D;.;.;.;.;.;.;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;.;D;D;.;.;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;.
Polyphen		1.0	D;D;D;D;D;D;D;.
Vest4		0.97
MutPred		0.73		Gain of helix (P = 0.0325);.;.;.;.;.;.;.;
MVP		0.84
MPC		1.5
ClinPred		0.93	D
GERP RS		6.1
Varity_R		0.72
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.87
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: rs779204091; hg19: chr9-98241428;