17-31260433-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4BS2_Supporting

The NM_001042492.3(NF1):​c.4495A>G​(p.Ile1499Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000082 ( 0 hom. )

Consequence

NF1
NM_001042492.3 missense

Scores

3
7
9

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 8.69
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

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.
BP4
Computational evidence support a benign effect (MetaRNN=0.39379504).
BS2
High AC in GnomAdExome4 at 12 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.4495A>G p.Ile1499Val missense_variant Exon 34 of 58 ENST00000358273.9 NP_001035957.1 P21359-1
NF1NM_000267.3 linkc.4432A>G p.Ile1478Val missense_variant Exon 33 of 57 NP_000258.1 P21359-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NF1ENST00000358273.9 linkc.4495A>G p.Ile1499Val missense_variant Exon 34 of 58 1 NM_001042492.3 ENSP00000351015.4 P21359-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251294
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135804
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000821
AC:
12
AN:
1461722
Hom.:
0
Cov.:
31
AF XY:
0.00000963
AC XY:
7
AN XY:
727160
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:
0.0000116
Gnomad4 FIN exome
AF:
0.0000562
Gnomad4 NFE exome
AF:
0.00000630
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Neurofibromatosis, type 1 Uncertain:1Benign:1
Nov 05, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely 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

- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Uncertain:1
Dec 13, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.4432A>G (p.I1478V) alteration is located in exon 33 (coding exon 33) of the NF1 gene. This alteration results from a A to G substitution at nucleotide position 4432, causing the isoleucine (I) at amino acid position 1478 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hereditary cancer-predisposing syndrome Uncertain:1
Jul 18, 2014
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.I1499V variant (also known as c.4495A>G), located in coding exon 34 of the NF1 gene, results from an A to G substitution at nucleotide position 4495. The isoleucine at codon 1499 is replaced by valine, 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 0.01% (greater than 11000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be benign and tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.I1499V remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Uncertain
0.081
D
BayesDel_noAF
Benign
-0.11
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.46
T;.;T
Eigen
Benign
0.093
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.92
D;D;D
M_CAP
Pathogenic
0.39
D
MetaRNN
Benign
0.39
T;T;T
MetaSVM
Uncertain
-0.26
T
MutationAssessor
Benign
1.2
L;.;.
PrimateAI
Pathogenic
0.82
D
PROVEAN
Benign
-0.53
N;N;N
REVEL
Uncertain
0.32
Sift
Benign
0.37
T;T;T
Sift4G
Benign
0.34
T;T;T
Polyphen
0.087
B;P;.
Vest4
0.49
MutPred
0.47
Gain of catalytic residue at I1499 (P = 0.0571);.;.;
MVP
0.72
MPC
1.2
ClinPred
0.42
T
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.13
gMVP
0.52

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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: rs764654925; hg19: chr17-29587451; API