rs199474762

Positions:

• chr17-31227254-T-C
• chr17-31227254-T-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001042492.3(NF1):​c.2288T>C​(p.Leu763Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 7.58

Genes affected

NF1 (HGNC:7765): (neurofibromin 1) This gene product appears to function as a negative regulator of the ras signal transduction pathway. Mutations in this gene have been linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. The mRNA for this gene is subject to RNA editing (CGA>UGA->Arg1306Term) resulting in premature translation termination. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene. [provided by RefSeq, Jul 2008]

NF1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 15 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), NF1. . Gene score misZ 6.5427 (greater than the threshold 3.09). Trascript score misZ 8.4054 (greater than threshold 3.09). GenCC has associacion of gene with neurofibromatosis, familial spinal, hereditary pheochromocytoma-paraganglioma, neurofibromatosis type 1, Watson syndrome, neurofibromatosis-Noonan syndrome, Moyamoya disease, familial ovarian cancer.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 17-31227254-T-C is Pathogenic according to our data. Variant chr17-31227254-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.2288T>C	p.Leu763Pro	missense_variant	19/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.2288T>C	p.Leu763Pro	missense_variant	19/57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.2288T>C	p.Leu763Pro	missense_variant	19/58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461430 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727034

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Aug 15, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 16, 2023	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 763 of the NF1 protein (p.Leu763Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10712197, 16005615, 21354044, 30530636, 31370276; Invitae). ClinVar contains an entry for this variant (Variation ID: 68312). 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 expected to disrupt NF1 protein function. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 30, 2015	The p.Leu763Pro variant in NF1 has been reported in 2 individuals with Neurofibr omatosis type 1, with an apparently de novo occurence in one of these individual s (Fahsold 2000, Valero 2011). This variant was absent from large population stu dies. Computational prediction tools and conservation analysis do not provide st rong support for or against an impact to the protein. In summary, although addit ional studies are required to fully establish its clinical significance, the p.L eu763Pro variant is likely pathogenic. -

not provided Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2018	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in multiple unrelated patients with a clinical diagnosis of neurofibromatosis type 1 (Fahsold et al., 2000; Frayling et al., 2019; Giugliano et al., 2019; Kang et al., 2020); This variant is associated with the following publications: (PMID: 24803665, 31370276, 25486365, 30530636, 32107864, 16005615, 21354044, 31776437, 10712197) -

not specified Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 27, 2018

The NF1 c.2288T>C; p.Leu763Pro variant (rs199474762) has been described in individuals affected with neurofibromatosis type 1, and segregating with disease in at least one family (Cai 2005, Fashold 2000, Valero 2011). It is reported as pathogenic/likely pathogenic in ClinVar (Variation ID: 68312) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The leucine at codon 763 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Based on available information, this variant is considered likely pathogenic. REFERENCES Cai Y et al. Two novel mutations of the NF1 gene in Chinese Han families with type 1 neurofibromatosis. J Dermatol Sci. 2005 Aug;39(2):125-7. Fashold R et al. Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. Am J Hum Genet. 2000 Mar;66(3):790-818. Valero M et al. A highly sensitive genetic protocol to detect NF1 mutations. J Mol Diagn. 2011 Mar;13(2):113-22. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 2016

The p.L763P pathogenic mutation (also known as c.2288T>C), located in coding exon 19 of the NF1 gene, results from a T to C substitution at nucleotide position 2288. The leucine at codon 763 is replaced by proline, an amino acid with similar properties. This mutation has been observed in multiple individuals meeting clinical NF1 diagnostic criteria, including an apparent de novo mutation in one affected individual with unaffected parents (Fahsold R, Am. J. Hum. Genet. 2000 Mar; 66(3):790-818; Valero MC, J Mol Diagn 2011 Mar; 13(2):113-22).<span style="background-color:initial">Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, p.L763P is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;.;D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.4	M;M;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.5	D;D;D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		1.0
MutPred		0.85		Gain of loop (P = 0.002);Gain of loop (P = 0.002);.;
MVP		0.97
MPC		2.2
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.96
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs199474762; hg19: chr17-29554272;