rs1060500252
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate
The NM_001042492.3(NF1):c.1A>C(p.Met1?) variant causes a initiator codon change involving the alteration of a non-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 Likely pathogenic (★).
Frequency
Genomes: not found (cov: 30)
Consequence
NF1
NM_001042492.3 initiator_codon
NM_001042492.3 initiator_codon
Scores
5
4
7
Clinical Significance
Conservation
PhyloP100: 2.60
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 Pathogenic. Variant got 14 ACMG points.
PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_001042492.3 (NF1) was described as [Pathogenic] in Lovd
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-31095310-A-C is Pathogenic according to our data. Variant chr17-31095310-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 694505.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.1A>C | p.Met1? | initiator_codon_variant | 1/58 | ENST00000358273.9 | NP_001035957.1 | |
NF1 | NM_000267.3 | c.1A>C | p.Met1? | initiator_codon_variant | 1/57 | NP_000258.1 | ||
NF1 | NM_001128147.3 | c.1A>C | p.Met1? | initiator_codon_variant | 1/15 | NP_001121619.1 | ||
MIR4733HG | NR_186435.1 | n.181T>G | non_coding_transcript_exon_variant | 1/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.1A>C | p.Met1? | initiator_codon_variant | 1/58 | 1 | NM_001042492.3 | ENSP00000351015.4 |
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD3 genomes
Cov.:
30
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 30
GnomAD4 genome
Cov.:
30
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Medical Molecular Genetics Department, National Research Center | - | - - |
Likely pathogenic, no assertion criteria provided | research | Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Benign
DEOGEN2
Uncertain
.;D;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Benign
T
PROVEAN
Benign
.;N;N;N
REVEL
Uncertain
Sift
Pathogenic
.;D;D;D
Sift4G
Pathogenic
.;D;D;D
Polyphen
P;D;B;.
Vest4
0.64, 0.60, 0.69
MutPred
Loss of MoRF binding (P = 0.0789);Loss of MoRF binding (P = 0.0789);Loss of MoRF binding (P = 0.0789);Loss of MoRF binding (P = 0.0789);
MVP
0.83
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