rs201605273

Positions:

• chr9-95453581-C-G
• chr9-95453581-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM2 PP2 BP4 BP6 BS2

The NM_000264.5(PTCH1):​c.3346G>C​(p.Val1116Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.94

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]

PTCH1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 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=0.35407692).
• BP6: Variant 9-95453581-C-G is Benign according to our data. Variant chr9-95453581-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2154676.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.3346G>C	p.Val1116Leu	missense_variant	20/24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.3343G>C	p.Val1115Leu	missense_variant	20/24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.3346G>C	p.Val1116Leu	missense_variant	20/24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.3343G>C	p.Val1115Leu	missense_variant	20/24	5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 250984 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135716

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

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: 0.00000342 AC: 5 AN: 1461750 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727170

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 20, 2024

The p.V1116L variant (also known as c.3346G>C), located in coding exon 20 of the PTCH1 gene, results from a G to C substitution at nucleotide position 3346. The valine at codon 1116 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Gorlin syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;.;.;.;.;.;.
Eigen	Benign	0.030
Eigen_PC	Benign	0.066
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;.;T;T;.;.;T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.35	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	0.55	N;.;.;.;.;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.79	N;N;N;N;N;N;N
REVEL	Uncertain	0.61
Sift	Benign	0.33	T;T;T;T;T;T;T
Sift4G	Benign	0.30	T;T;T;T;T;T;T
Polyphen		0.80	P;.;.;P;P;.;P
Vest4		0.40
MutPred		0.52		Loss of ubiquitination at K1111 (P = 0.1264);.;.;.;.;.;.;
MVP		0.69
MPC		0.58
ClinPred		0.41	T
GERP RS		3.3
Varity_R		0.21
gMVP		0.74

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: rs201605273; hg19: chr9-98215863; COSMIC: COSV59480459; COSMIC: COSV59480459;