17-31327839-G-C

Variant names:

• chr17-31327839-G-C
• NM_001042492.3:c.5609G>C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_001042492.3(NF1):​c.5609G>C​(p.Arg1870Pro) variant causes a missense, splice region 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. 14/25 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. R1870L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NF1 NM_001042492.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• 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 12 ACMG points.

• PM1: In a helix (size 16) in uniprot entity NF1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001042492.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-31327839-G-T 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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 17-31327839-G-C is Pathogenic according to our data. Variant chr17-31327839-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1748220.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr17-31327839-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.5609G>C	p.Arg1870Pro	missense_variant, splice_region_variant	Exon 38 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.5546G>C	p.Arg1849Pro	missense_variant, splice_region_variant	Exon 37 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.5609G>C	p.Arg1870Pro	missense_variant, splice_region_variant	Exon 38 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:2 Uncertain:1

Aug 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant disrupts the c.5546G nucleotide in the NF1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 10607834, 10980545, 27322474; Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. ClinVar contains an entry for this variant (Variation ID: 1748220). This missense change has been observed in individual(s) with clinical features of neurofibromatosis type 1 (PMID: 23913538). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1849 of the NF1 protein (p.Arg1849Pro). This variant also falls at the last nucleotide of exon 37, which is part of the consensus splice site for this exon. -

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Department of Medical Genetics, College of Basic Medicine, Army Medical University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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Apr 09, 2025

NHS Central & South Genomic Laboratory Hub

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 09, 2022

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5546G>C variant (also known as p.R1849P), located in coding exon 37 of the NF1 gene, results from a G to C substitution at nucleotide position 5546. The amino acid change results in arginine to proline at codon 1849, an amino acid with dissimilar properties. However, this change occurs in the last base pair of coding exon 37, which makes it likely to have some effect on normal mRNA splicing. This variant was identified in 1 of 565 unrelated French probands with clinical diagnoses or suspicion of neurofibromatosis type 1 (Sabbagh A et al. Hum Mutat, 2013 Nov;34:1510-8). In silico splice site analysis predicts that this alteration may weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Pathogenic	3.3	M;.;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.0	D;D;D;.
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;.
Polyphen		1.0	D;D;.;.
Vest4		0.98
MutPred		0.62		Gain of glycosylation at R1870 (P = 0.01);.;.;.;
MVP		0.93
MPC		2.7
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.39		Position offset: 0

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-29654857;