17-31227539-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM5PP2BS2_Supporting

The NM_001042492.3(NF1):​c.2342A>T​(p.His781Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,613,752 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. H781P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

NF1
NM_001042492.3 missense

Scores

2
4
13

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 6.80
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 Uncertain_significance. Variant got 4 ACMG points.

PM1
In a helix (size 21) in uniprot entity NF1_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_001042492.3
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-31227539-A-C is described in Lovd as [Pathogenic].
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NF1. . Gene score misZ 6.5427 (greater than the threshold 3.09). Trascript score misZ 8.4054 (greater than threshold 3.09). GenCC has associacion of gene with neurofibromatosis, familial spinal, hereditary pheochromocytoma-paraganglioma, neurofibromatosis type 1, Watson syndrome, neurofibromatosis-Noonan syndrome, Moyamoya disease, familial ovarian cancer.
BS2
High AC in GnomAdExome4 at 10 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/exons MANE Protein UniProt
NF1NM_001042492.3 linkuse as main transcriptc.2342A>T p.His781Leu missense_variant 20/58 ENST00000358273.9 NP_001035957.1 P21359-1
NF1NM_000267.3 linkuse as main transcriptc.2342A>T p.His781Leu missense_variant 20/57 NP_000258.1 P21359-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NF1ENST00000358273.9 linkuse as main transcriptc.2342A>T p.His781Leu missense_variant 20/581 NM_001042492.3 ENSP00000351015.4 P21359-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152242
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000684
AC:
10
AN:
1461510
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
727062
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:
0.00000899
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152242
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74366
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Neurofibromatosis, type 1 Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 07, 2023This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 781 of the NF1 protein (p.His781Leu). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 216398). 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 not expected to disrupt NF1 protein function with a negative predictive value of 95%. 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. -
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabMar 15, 2022- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMar 26, 2024In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed as a germline variant in an adult patient with AML; however, no further clinical information was provided (PMID: 34482403); This variant is associated with the following publications: (PMID: 25486365, 34482403) -
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 25, 2020The c.2342A>T (p.H781L) alteration is located in exon 20 (coding exon 20) of the NF1 gene. This alteration results from a A to T substitution at nucleotide position 2342, causing the histidine (H) at amino acid position 781 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 16, 2015The p.H781L variant (also known as c.2342A>T), located in coding exon 20 of the NF1 gene, results from an A to T substitution at nucleotide position 2342. The histidine at codon 781 is replaced by leucine, an amino acid with similar properties. A similar alteration at the same codon, p.H781P, has been reported in a patient with neurofibromatosis type 1 (NF1) (Fahsold R et al. Am J Hum Genet. 2000 Mar;66(3):790-818).The p.H781Lvariant 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 0.002% (greater than 55000alleles tested) in our clinical cohort.This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.Since supporting evidence is limited at this time, the clinical significance of p.H781Lremains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Uncertain
0.090
D
BayesDel_noAF
Benign
-0.11
CADD
Benign
22
DANN
Benign
0.96
DEOGEN2
Uncertain
0.65
D;.;T
Eigen
Benign
-0.14
Eigen_PC
Benign
0.078
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.85
T;T;T
M_CAP
Benign
0.081
D
MetaRNN
Uncertain
0.46
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.69
N;N;.
PrimateAI
Pathogenic
0.79
T
PROVEAN
Uncertain
-2.8
D;D;N
REVEL
Benign
0.26
Sift
Benign
0.26
T;T;T
Sift4G
Benign
0.48
T;T;T
Polyphen
0.0
B;B;.
Vest4
0.76
MVP
0.82
MPC
0.86
ClinPred
0.90
D
GERP RS
4.8
Varity_R
0.17
gMVP
0.86

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: rs199474763; hg19: chr17-29554557; API