NM_001042492.3:c.2990G>A

Variant names:

• chr17-31229974-G-A
• rs1555614462
• NM_001042492.3:c.2990G>A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001042492.3(NF1):​c.2990G>A​(p.Arg997Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense, splice_region
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.56

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 Pathogenic. Variant got 15 ACMG points.

• PM1: In a helix (size 10) in uniprot entity NF1_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_001042492.3
• PM2: Very rare variant in population databases, with high coverage
• 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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 17-31229974-G-A is Pathogenic according to our data. Variant chr17-31229974-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 654334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31229974-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.2990G>A	p.Arg997Lys	missense_variant, splice_region_variant	Exon 22 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.2990G>A	p.Arg997Lys	missense_variant, splice_region_variant	Exon 22 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.2990G>A	p.Arg997Lys	missense_variant, splice_region_variant	Exon 22 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:3

Apr 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 997 of the NF1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NF1 protein. This variant also falls at the last nucleotide of exon 22, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with neurofibromatosis type 1 (PMID: 23913538, 29673180, 35121649; Invitae). ClinVar contains an entry for this variant (Variation ID: 654334). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with inconclusive levels of altered splicing (PMID: 23913538). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Mar 15, 2022

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 11, 2024

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Oct 03, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28068329, 25486365, 2121369, 29673180, 23913538, Kiraz_2023, 35121649) -

Nov 11, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NF1 c.2990G>A; p.Arg997Lys variant (rs1555614462, ClinVar Variation ID: 654334) is reported in the literature in several individuals affected with NF1 or suspected NF1 (Kiraz 2023, Sabbagh 2013, Stella 2018) and in an individual with juvenile myelomonocytic leukemia that also carried a somatic NF1 variant (Wang 2023). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant occurs at the last nucleotide of exon 22 and computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. Consistent with predictions, mRNA analysis from patient cells indicates this variant leads to skipping of exon 22 (reported as exon 17, Sabbagh 2013). Other variants impacting this splice donor site (c.2990+1G>A, c.2990+1G>C, and c.2990G>C; p.Arg997Thr) have also been reported in patients with clinical features of neurofibromatosis type 1 (Assunto 2019, Palma Milla 2018, Sabbagh 2013). Based on available information, the p.Arg997Lys variant is considered to be likely pathogenic. References: Assunto A et al. Isoform-specific NF1 mRNA levels correlate with disease severity in Neurofibromatosis type 1. Orphanet J Rare Dis. 2019 Nov 15;14(1):261. PMID: 31730495. Kiraz A et al. Detection of Novel NF1 Variants with Next-Generation DNA Sequencing Technology and Genotype–Phenotype Characteristics of Neurofibromatosis. J Clin Pract Res. 2023; 45(2):152-158. Palma Milla C et al. Neurofibromatosis type I: mutation spectrum of NF1 in spanish patients. Ann Hum Genet. 2018 Nov;82(6):425-436. PMID: 30014477. Sabbagh A et al. NF1 molecular characterization and neurofibromatosis type I genotype-phenotype correlation: the French experience. Hum Mutat. 2013 Nov;34(11):1510-8. PMID: 23913538. Stella A et al. Accurate Classification of NF1 Gene Variants in 84 Italian Patients with Neurofibromatosis Type 1. Genes (Basel). 2018 Apr 17;9(4):216. PMID: 29673180. Wang W et al. Germline Neurofibromin 1 mutation enhances the anti-tumour immune response and decreases juvenile myelomonocytic leukaemia tumourigenicity. Br J Haematol. 2023 Jul;202(2):328-343. PMID: 37144690. -

Juvenile myelomonocytic leukemia Pathogenic:1

Apr 20, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1

Dec 04, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2990G>A pathogenic mutation (also known as p.R997K), located in coding exon 22 of the NF1 gene, results from a G to A substitution at nucleotide position 2990. The amino acid change results in arginine to lysine at codon 997, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 22, which makes it likely to have some effect on normal mRNA splicing. This variant was reported in individual(s) with features consistent with neurofibromatosis type 1 (Sabbagh A et al. Hum. Mutat., 2013 Nov;34:1510-8; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. Functional RNA studies showed aberrant splicing resulting in exon skipping (Sabbagh A et al. Hum. Mutat., 2013 Nov;34:1510-8; Ambry internal data) Based on the available evidence, this variant is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.00028	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;.;T
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.5	L;L;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.27
Sift	Benign	0.35	T;T;T
Sift4G	Benign	0.078	T;T;T
Polyphen		0.98	D;P;.
Vest4		0.69
MutPred		0.43		Gain of ubiquitination at R997 (P = 0.0146);Gain of ubiquitination at R997 (P = 0.0146);.;
MVP		0.70
MPC		1.6
ClinPred		0.92	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.37
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.36		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555614462; hg19: chr17-29556992;