rs1465309384

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3

The NM_001042492.3(NF1):​c.5705C>A​(p.Ala1902Asp) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1902G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

NF1
NM_001042492.3 missense

Scores

9
8
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.54
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 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, 0.808

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NF1NM_001042492.3 linkuse as main transcriptc.5705C>A p.Ala1902Asp missense_variant 39/58 ENST00000358273.9
NF1NM_000267.3 linkuse as main transcriptc.5642C>A p.Ala1881Asp missense_variant 38/57

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NF1ENST00000358273.9 linkuse as main transcriptc.5705C>A p.Ala1902Asp missense_variant 39/581 NM_001042492.3 P1P21359-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 18, 2019The p.A1881D variant (also known as c.5642C>A), located in coding exon 38 of the NF1 gene, results from a C to A substitution at nucleotide position 5642. The alanine at codon 1881 is replaced by aspartic acid, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.48
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.77
D;.;T;.
Eigen
Uncertain
0.48
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.93
D;D;D;D
M_CAP
Pathogenic
0.87
D
MetaRNN
Pathogenic
0.81
D;D;D;D
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Benign
2.0
M;.;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.90
D
PROVEAN
Uncertain
-3.1
D;D;D;.
REVEL
Pathogenic
0.76
Sift
Uncertain
0.018
D;D;D;.
Sift4G
Uncertain
0.0050
D;D;D;.
Polyphen
0.12
B;D;.;.
Vest4
0.89
MutPred
0.40
Gain of solvent accessibility (P = 0.1708);.;.;.;
MVP
0.93
MPC
2.8
ClinPred
0.97
D
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.56
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
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: rs1465309384; hg19: chr17-29657409; COSMIC: COSV62202612; API