NM_001042492.3:c.1780A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001042492.3(NF1):​c.1780A>G​(p.Thr594Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,770 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T594P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NF1
NM_001042492.3 missense

Scores

4
9
6

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 6.70

Publications

0 publications found
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]
NF1 Gene-Disease associations (from GenCC):
  • neurofibromatosis type 1
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
  • neurofibromatosis-Noonan syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
  • Moyamoya disease
    Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
  • hereditary pheochromocytoma-paraganglioma
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • familial ovarian cancer
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NF1NM_001042492.3 linkc.1780A>G p.Thr594Ala missense_variant Exon 16 of 58 ENST00000358273.9 NP_001035957.1 P21359-1
NF1NM_000267.4 linkc.1780A>G p.Thr594Ala missense_variant Exon 16 of 57 NP_000258.1 P21359-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NF1ENST00000358273.9 linkc.1780A>G p.Thr594Ala missense_variant Exon 16 of 58 1 NM_001042492.3 ENSP00000351015.4 P21359-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460770
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
726736
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33430
American (AMR)
AF:
0.00
AC:
0
AN:
44690
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26098
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39600
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86234
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53400
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5750
European-Non Finnish (NFE)
AF:
9.00e-7
AC:
1
AN:
1111240
Other (OTH)
AF:
0.00
AC:
0
AN:
60328
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Neurofibromatosis, type 1 Uncertain:2
Mar 15, 2022
Genome-Nilou Lab
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Apr 15, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 594 of the NF1 protein (p.Thr594Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 457546). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NF1 protein function. 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. -

not provided Uncertain:1
Jul 29, 2019
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.020
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.78
D;.;T
Eigen
Uncertain
0.68
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.94
D;D;D
M_CAP
Pathogenic
0.44
D
MetaRNN
Uncertain
0.53
D;D;D
MetaSVM
Uncertain
-0.25
T
MutationAssessor
Benign
1.7
L;L;.
PhyloP100
6.7
PrimateAI
Uncertain
0.76
T
PROVEAN
Uncertain
-2.8
D;D;D
REVEL
Benign
0.23
Sift
Benign
0.32
T;T;T
Sift4G
Benign
0.21
T;T;T
Polyphen
0.98
D;D;.
Vest4
0.81
MutPred
0.23
Loss of methylation at K598 (P = 0.0831);Loss of methylation at K598 (P = 0.0831);.;
MVP
0.87
MPC
1.7
ClinPred
0.99
D
GERP RS
5.3
Varity_R
0.31
gMVP
0.29
Mutation Taster
=4/96
disease causing

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

Other links and lift over

dbSNP: rs1555613419; hg19: chr17-29550520; API