17-31182623-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001042492.3(NF1):​c.846G>C​(p.Gln282His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q282K) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

NF1
NM_001042492.3 missense

Scores

5
14

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.844
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 1 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.
BP4
Computational evidence support a benign effect (MetaRNN=0.15948054).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NF1NM_001042492.3 linkuse as main transcriptc.846G>C p.Gln282His missense_variant 8/58 ENST00000358273.9
NF1NM_000267.3 linkuse as main transcriptc.846G>C p.Gln282His missense_variant 8/57
NF1NM_001128147.3 linkuse as main transcriptc.846G>C p.Gln282His missense_variant 8/15

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NF1ENST00000358273.9 linkuse as main transcriptc.846G>C p.Gln282His missense_variant 8/581 NM_001042492.3 P1P21359-1

Frequencies

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.27
BayesDel_addAF
Benign
-0.022
T
BayesDel_noAF
Benign
-0.27
CADD
Benign
16
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.56
.;D;.;.;.
Eigen
Benign
-0.16
Eigen_PC
Benign
0.028
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Uncertain
0.93
D;D;D;D;D
M_CAP
Benign
0.072
D
MetaRNN
Benign
0.16
T;T;T;T;T
MetaSVM
Benign
-0.93
T
MutationAssessor
Benign
0.40
N;N;N;N;.
MutationTaster
Benign
0.98
D;D;D
PrimateAI
Uncertain
0.70
T
PROVEAN
Benign
-1.1
.;N;N;N;.
REVEL
Benign
0.12
Sift
Benign
0.045
.;D;D;D;.
Sift4G
Benign
0.085
.;T;T;T;.
Polyphen
0.0020
B;B;B;.;.
Vest4
0.28, 0.30, 0.32
MutPred
0.34
Loss of solvent accessibility (P = 0.0561);Loss of solvent accessibility (P = 0.0561);Loss of solvent accessibility (P = 0.0561);Loss of solvent accessibility (P = 0.0561);.;
MVP
0.61
MPC
0.65
ClinPred
0.32
T
GERP RS
4.3
Varity_R
0.11
gMVP
0.32

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-29509641; API