NM_001042492.3:c.7262A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS2_Supporting

The NM_001042492.3(NF1):​c.7262A>G​(p.Asn2421Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N2421D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

NF1
NM_001042492.3 missense

Scores

3
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 6.81

Publications

3 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: Likely_benign. The variant received -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.07091951).
BS2
High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NF1NM_001042492.3 linkc.7262A>G p.Asn2421Ser missense_variant Exon 49 of 58 ENST00000358273.9 NP_001035957.1 P21359-1
NF1NM_000267.4 linkc.7199A>G p.Asn2400Ser missense_variant Exon 48 of 57 NP_000258.1 P21359-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NF1ENST00000358273.9 linkc.7262A>G p.Asn2421Ser missense_variant Exon 49 of 58 1 NM_001042492.3 ENSP00000351015.4 P21359-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000399
AC:
1
AN:
250668
AF XY:
0.00000738
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000882
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461286
Hom.:
0
Cov.:
32
AF XY:
0.00000413
AC XY:
3
AN XY:
726944
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33470
American (AMR)
AF:
0.00
AC:
0
AN:
44696
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26114
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39674
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86186
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53270
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5764
European-Non Finnish (NFE)
AF:
0.00000450
AC:
5
AN:
1111736
Other (OTH)
AF:
0.00
AC:
0
AN:
60376
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.535
Heterozygous variant carriers
0
1
1
2
2
3
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
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Neurofibromatosis, type 1 Uncertain:1Benign:1
May 06, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

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

- -

not specified Uncertain:1
May 04, 2022
Mendelics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Uncertain:1
Jul 08, 2022
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.7199A>G (p.N2400S) alteration is located in exon 48 (coding exon 48) of the NF1 gene. This alteration results from a A to G substitution at nucleotide position 7199, causing the asparagine (N) at amino acid position 2400 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hereditary cancer-predisposing syndrome Uncertain:1
Apr 09, 2015
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.N2421S variant (also known as c.7262A>G), located in coding exon 49 of the NF1 gene, results from an A to G substitution at nucleotide position 7262. The asparagine at codon 2421 is replaced by serine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.003% (greater than 30000alleles tested) in our clinical cohort.This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis.Since supporting evidence is limited at this time, the clinical significance of p.N2421Sremains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.050
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.72
CADD
Benign
20
DANN
Benign
0.87
DEOGEN2
Benign
0.39
T;.;T
Eigen
Benign
-0.32
Eigen_PC
Benign
-0.051
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.96
D;D;D
M_CAP
Benign
0.039
D
MetaRNN
Benign
0.071
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
-1.2
N;.;.
PhyloP100
6.8
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
0.68
N;N;N
REVEL
Benign
0.084
Sift
Benign
0.78
T;T;T
Sift4G
Benign
0.48
T;T;T
Polyphen
0.0
B;B;.
Vest4
0.11
MutPred
0.34
Gain of catalytic residue at K2422 (P = 0.0461);.;.;
MVP
0.31
MPC
0.40
ClinPred
0.41
T
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.058
gMVP
0.18
Mutation Taster
=83/17
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs774339063; hg19: chr17-29676210; API