9-95446976-A-G

Position:

• chr9-95446976-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000264.5(PTCH1):​c.4280T>C​(p.Val1427Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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. V1427L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.87

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 1 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=0.19157296).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH1	NM_000264.5	c.4280T>C	p.Val1427Ala	missense_variant	23/24	ENST00000331920.11
PTCH1	NM_001083603.3	c.4277T>C	p.Val1426Ala	missense_variant	23/24	ENST00000437951.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11	c.4280T>C	p.Val1427Ala	missense_variant	23/24	5	NM_000264.5	A2
PTCH1	ENST00000437951.6	c.4277T>C	p.Val1426Ala	missense_variant	23/24	5	NM_001083603.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Jul 29, 2023

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. 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. ClinVar contains an entry for this variant (Variation ID: 409174). This variant has not been reported in the literature in individuals affected with PTCH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1427 of the PTCH1 protein (p.Val1427Ala). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 12, 2022

The p.V1427A variant (also known as c.4280T>C), located in coding exon 23 of the PTCH1 gene, results from a T to C substitution at nucleotide position 4280. The valine at codon 1427 is replaced by alanine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. 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	0.11
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.;.;.;.;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T;.;T;T;.;.;T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.8	L;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.69	N;N;N;N;N;N;N
REVEL	Uncertain	0.42
Sift	Benign	0.073	T;T;T;T;T;T;T
Sift4G	Uncertain	0.012	D;D;D;D;D;D;D
Polyphen		0.051	B;.;.;B;B;.;B
Vest4		0.24
MutPred		0.52		Loss of sheet (P = 0.0104);.;.;.;.;.;.;
MVP		0.24
MPC		0.092
ClinPred		0.67	D
GERP RS		5.1
Varity_R		0.080
gMVP		0.35

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: rs1060502283; hg19: chr9-98209258;