17-31201113-T-G

Variant names:

• chr17-31201113-T-G
• rs1555611004
• NM_001042492.3:c.1139T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP2 PP3_Moderate PP5

The NM_001042492.3(NF1):​c.1139T>G​(p.Leu380Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L380P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 7.64

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-31201113-T-C is described in Lovd as [Pathogenic].
• PP2: Missense variant in the NF1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 399 curated pathogenic missense variants (we use a threshold of 10). The gene has 143 curated benign missense variants. Gene score misZ: 6.5427 (above the threshold of 3.09). Trascript score misZ: 8.4054 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.883
• PP5: Variant 17-31201113-T-G is Pathogenic according to our data. Variant chr17-31201113-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 993576.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.1139T>G	p.Leu380Arg	missense_variant	Exon 10 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.1139T>G	p.Leu380Arg	missense_variant	Exon 10 of 57		NP_000258.1
NF1	NM_001128147.3	c.1139T>G	p.Leu380Arg	missense_variant	Exon 10 of 15		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.1139T>G	p.Leu380Arg	missense_variant	Exon 10 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:1 Uncertain:1

Mar 15, 2022

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu380 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21520333, 27999334; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 993576). This missense change has been observed in individual(s) with neurofibromatosis type 1 (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 380 of the NF1 protein (p.Leu380Arg). -

NF1-related disorder Uncertain:1

May 23, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NF1 c.1139T>G variant is predicted to result in the amino acid substitution p.Leu380Arg. This variant has been reported as a germline variant in an individual with acute myeloid leukemia and suspected diagnosis of neurofibromatosis (Weinberg et al. 2019. PubMed ID: 31309983). This variant has been reported de novo (aparently mosaic), along with a pathogenic variant in another gene, in an individual undergoing testing for Noonan spectrum disorders/rasopathies (Internal Data, PreventionGenetics). This variant has not been reported in a large population database, indicating this variant is rare. This variant has conflicting interpretations of pathogenicity in ClinVar of uncertain and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/993576/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1

Jul 14, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NF1 c.1139T>G; p.Leu380Arg variant is reported in the literature in an individual affected with acute myeloid leukemia with a suspected diagnosis of neurofibromatosis type 1 (Weinberg 2019). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The leucine at codon 380 is moderately conserved, and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Additionally, another amino acid substitution at this codon (p.Leu380Pro) has been reported in several probands with neurofibromatosis type 1 and segregated with disease in members of one family (Cunha 2016, Frayling 2019). However, given the lack of clinical and functional data, the significance of the p.Leu380Arg variant is uncertain at this time. References: Cunha KS et al. Hybridization Capture-Based Next-Generation Sequencing to Evaluate Coding Sequence and Deep Intronic Mutations in the NF1 Gene. Genes (Basel). 2016;7(12):133. Frayling IM et al. Breast cancer risk in neurofibromatosis type 1 is a function of the type of NF1 gene mutation: a new genotype-phenotype correlation. J Med Genet. 2019;56(4):209-219. Weinberg OK et al. Germline Predisposition to Hematolymphoid Neoplasia. Am J Clin Pathol. 2019;152(3):258-276. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	.;D;.;.;D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	1.1	L;L;L;L;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.5	.;D;D;D;N
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	.;D;D;D;D
Sift4G	Pathogenic	0.0	.;D;D;D;D
Polyphen		0.83	P;B;P;.;.
Vest4		0.97, 0.97, 0.95
MutPred		0.65		Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);.;
MVP		0.98
MPC		1.2
ClinPred		0.96	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.71
gMVP		0.94

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: rs1555611004; hg19: chr17-29528131;