17-31230373-T-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong

The NM_001042492.3(NF1):​c.3104T>G​(p.Met1035Arg) variant causes a missense change involving the alteration of a 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: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

NF1
NM_001042492.3 missense

Scores

9
8
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.64
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 Pathogenic. Variant got 13 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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.93
PP5
Variant 17-31230373-T-G is Pathogenic according to our data. Variant chr17-31230373-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NF1NM_001042492.3 linkc.3104T>G p.Met1035Arg missense_variant Exon 23 of 58 ENST00000358273.9 NP_001035957.1 P21359-1
NF1NM_000267.3 linkc.3104T>G p.Met1035Arg missense_variant Exon 23 of 57 NP_000258.1 P21359-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NF1ENST00000358273.9 linkc.3104T>G p.Met1035Arg missense_variant Exon 23 of 58 1 NM_001042492.3 ENSP00000351015.4 P21359-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
6.84e-7
AC:
1
AN:
1461118
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726856
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00152
Hom.:
0

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:4
Jul 20, 2024
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The NF1 c.3104T>G (p.Met1035Arg) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with neurofibromatosis type 1 and LEOPARD syndrome, suggesting that the phenotype associated with this variant may be broader than traditional NF1 (PMID: 8807336; 31766501). ?In summary, this variant meets criteria to be classified as likely pathogenic.? -

Jan 01, 1996
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Sep 27, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1035 of the NF1 protein (p.Met1035Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with neurofibromatosis type I (NF1), Neurofibromatosis-Noonan syndrome (NFNS), and/or Noonan syndrome with multiple lentigines (LEOPARD syndrome) (PMID: 8807336; Invitae). ClinVar contains an entry for this variant (Variation ID: 347). 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) performed at Invitae indicates that this missense variant is expected to disrupt NF1 protein function. This variant disrupts the p.Met1035 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9042399, 24789688; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Mar 26, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:1
Sep 10, 2024
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16542390, 24803665, 24789688, 9042399, 31487937, 30843352, 25486365, 2121369, 31766501, 8807336) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.10
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.94
D;.;D
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.61
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;D;D
M_CAP
Pathogenic
0.70
D
MetaRNN
Pathogenic
0.93
D;D;D
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.5
M;M;.
PrimateAI
Pathogenic
0.91
D
PROVEAN
Uncertain
-4.2
D;D;D
REVEL
Pathogenic
0.68
Sift
Uncertain
0.0010
D;D;D
Sift4G
Pathogenic
0.0010
D;D;D
Polyphen
0.99
D;P;.
Vest4
0.97
MutPred
0.81
Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);.;
MVP
0.84
MPC
2.0
ClinPred
1.0
D
GERP RS
5.3
Varity_R
0.89
gMVP
0.91

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs137854553; hg19: chr17-29557391; API