17-31206337-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_001042492.3(NF1):​c.1358G>C​(p.Gly453Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

NF1
NM_001042492.3 missense

Scores

1
15
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 5.03
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 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the NF1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 399 curated pathogenic missense variants (we use a threshold of 10). The gene has 143 curated benign missense variants. Gene score misZ: 6.5427 (above the threshold of 3.09). Trascript score misZ: 8.4054 (above the threshold of 3.09). GenCC associations: The gene is linked to neurofibromatosis, familial spinal, hereditary pheochromocytoma-paraganglioma, neurofibromatosis type 1, Watson syndrome, neurofibromatosis-Noonan syndrome, Moyamoya disease, familial ovarian cancer.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NF1NM_001042492.3 linkc.1358G>C p.Gly453Ala missense_variant Exon 12 of 58 ENST00000358273.9 NP_001035957.1 P21359-1
NF1NM_000267.3 linkc.1358G>C p.Gly453Ala missense_variant Exon 12 of 57 NP_000258.1 P21359-2
NF1NM_001128147.3 linkc.1358G>C p.Gly453Ala missense_variant Exon 12 of 15 NP_001121619.1 P21359-5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NF1ENST00000358273.9 linkc.1358G>C p.Gly453Ala missense_variant Exon 12 of 58 1 NM_001042492.3 ENSP00000351015.4 P21359-1

Frequencies

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

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

NF1-related disorder Uncertain:1
Oct 28, 2023
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The NF1 c.1358G>C variant is predicted to result in the amino acid substitution p.Gly453Ala. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Uncertain:1
Feb 13, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.G453A variant (also known as c.1358G>C), located in coding exon 12 of the NF1 gene, results from a G to C substitution at nucleotide position 1358. The glycine at codon 453 is replaced by alanine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
-0.060
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.75
.;D;.;.;T
Eigen
Uncertain
0.27
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.90
D;D;D;D;D
M_CAP
Uncertain
0.13
D
MetaRNN
Uncertain
0.50
T;T;T;T;T
MetaSVM
Uncertain
0.31
D
MutationAssessor
Benign
1.7
L;L;L;L;.
PrimateAI
Uncertain
0.70
T
PROVEAN
Uncertain
-3.1
.;D;D;D;D
REVEL
Uncertain
0.38
Sift
Uncertain
0.010
.;D;D;T;D
Sift4G
Uncertain
0.010
.;D;D;T;D
Polyphen
0.0010
B;B;B;.;.
Vest4
0.49, 0.49, 0.29
MutPred
0.46
Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);.;
MVP
0.79
MPC
0.74
ClinPred
0.82
D
GERP RS
6.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.37
gMVP
0.35

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: chr17-29533355; API