rs1555534402
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_001042492.3(NF1):c.5885A>C(p.His1962Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. H1962R) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 29)
Consequence
NF1
NM_001042492.3 missense
NM_001042492.3 missense
Scores
1
9
9
Clinical Significance
Conservation
PhyloP100: 6.78
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.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, NF1
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.5885A>C | p.His1962Pro | missense_variant | 40/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.5822A>C | p.His1941Pro | missense_variant | 39/57 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.5885A>C | p.His1962Pro | missense_variant | 40/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 29
GnomAD3 genomes
?
Cov.:
29
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 29
GnomAD4 genome
?
Cov.:
29
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Neurofibromatosis, type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 28, 2019 | This sequence change replaces histidine with proline at codon 1941 of the NF1 protein (p.His1941Pro). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and proline. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with NF1-related conditions. This variant is not present in population databases (ExAC no frequency). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Benign
DEOGEN2
Uncertain
D;.;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.;.;.
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;.
REVEL
Uncertain
Sift
Benign
T;T;T;.
Sift4G
Benign
T;T;T;.
Polyphen
B;P;.;.
Vest4
MutPred
Gain of loop (P = 0.0195);.;.;.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at