rs1060500379

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1PM2PP2BP4_Moderate

The NM_001042492.3(NF1):​c.4010G>A​(p.Arg1337Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

NF1
NM_001042492.3 missense

Scores

4
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 3.21
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1
In a domain Ras-GAP (size 216) in uniprot entity NF1_HUMAN there are 42 pathogenic changes around while only 3 benign (93%) in NM_001042492.3
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). The gene has 399 curated pathogenic missense variants (we use a threshold of 10). The gene has 143 curated benign missense variants. GenCC has associacion of the gene with neurofibromatosis, familial spinal, hereditary pheochromocytoma-paraganglioma, neurofibromatosis type 1, Watson syndrome, neurofibromatosis-Noonan syndrome, Moyamoya disease, familial ovarian cancer.
BP4
Computational evidence support a benign effect (MetaRNN=0.21459514).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NF1NM_001042492.3 linkc.4010G>A p.Arg1337Gln missense_variant 30/58 ENST00000358273.9 NP_001035957.1 P21359-1
NF1NM_000267.3 linkc.4010G>A p.Arg1337Gln missense_variant 30/57 NP_000258.1 P21359-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NF1ENST00000358273.9 linkc.4010G>A p.Arg1337Gln missense_variant 30/581 NM_001042492.3 ENSP00000351015.4 P21359-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251160
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135734
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461826
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727216
show subpopulations
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:
0.0000166
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Neurofibromatosis, type 1 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabMar 15, 2022- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 02, 2025- -
NF1-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMar 27, 2024The NF1 c.4010G>A variant is predicted to result in the amino acid substitution p.Arg1337Gln. To our knowledge, this variant has not been reported in individuals with NF1 related disorders in the literature. This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/404606/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Neurofibromatosis, type 1;C0349639:Juvenile myelomonocytic leukemia;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 04, 2022- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMar 24, 2023Has not been observed in patients with NF1-related features to our knowledge, but has been reported in a control group (Momozawa et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29106415, 30287823, 25486365, 22807134) -
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 15, 2020The p.R1337Q variant (also known as c.4010G>A), located in coding exon 30 of the NF1 gene, results from a G to A substitution at nucleotide position 4010. The arginine at codon 1337 is replaced by glutamine, an amino acid with highly similar properties. This alteration was observed in 0/7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00009 in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.061
BayesDel_addAF
Benign
-0.071
T
BayesDel_noAF
Benign
-0.34
CADD
Uncertain
24
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.51
D;.;T
Eigen
Benign
-0.25
Eigen_PC
Benign
-0.033
FATHMM_MKL
Benign
0.65
D
LIST_S2
Uncertain
0.93
D;D;D
M_CAP
Uncertain
0.15
D
MetaRNN
Benign
0.21
T;T;T
MetaSVM
Benign
-0.81
T
MutationAssessor
Benign
0.66
N;N;.
PrimateAI
Benign
0.43
T
PROVEAN
Benign
-1.2
N;N;N
REVEL
Benign
0.12
Sift
Benign
0.59
T;T;T
Sift4G
Benign
0.55
T;T;T
Polyphen
0.056
B;B;.
Vest4
0.33
MutPred
0.44
Gain of disorder (P = 0.151);Gain of disorder (P = 0.151);.;
MVP
0.65
MPC
0.80
ClinPred
0.32
T
GERP RS
4.8
Varity_R
0.31
gMVP
0.34

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1060500379; hg19: chr17-29576037; API