chr17-31343037-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PP2PP3_StrongBS2_Supporting

The NM_001042492.3(NF1):​c.7091G>A​(p.Arg2364Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

NF1
NM_001042492.3 missense

Scores

8
10
1

Clinical Significance

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

Conservation

PhyloP100: 9.18
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.

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, 0.943
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/exons MANE Protein UniProt
NF1NM_001042492.3 linkc.7091G>A p.Arg2364Gln missense_variant 48/58 ENST00000358273.9 NP_001035957.1 P21359-1
NF1NM_000267.3 linkc.7028G>A p.Arg2343Gln missense_variant 47/57 NP_000258.1 P21359-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NF1ENST00000358273.9 linkc.7091G>A p.Arg2364Gln missense_variant 48/581 NM_001042492.3 ENSP00000351015.4 P21359-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152084
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.00000342
AC:
5
AN:
1461776
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727194
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:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152084
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74290
show subpopulations
Gnomad4 AFR
AF:
0.00
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

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:2Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 02, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabMar 15, 2022- -
Uncertain significance, criteria provided, single submitterclinical testingMendelicsJul 02, 2018- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJun 25, 2021In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Absent from cases but observed in controls in a breast cancer case-control study (Momozawa 2018); This variant is associated with the following publications: (PMID: 27535533, 30287823) -
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 24, 2023The p.R2343Q variant (also known as c.7028G>A), located in coding exon 47 of the NF1 gene, results from a G to A substitution at nucleotide position 7028. The arginine at codon 2343 is replaced by glutamine, an amino acid with highly similar properties. This alteration was observed with an allele frequency of 0 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00009 in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This alteration was also detected in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is highly 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 this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.92
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Uncertain
0.11
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.85
D;.;T
Eigen
Uncertain
0.47
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D;D;D
M_CAP
Pathogenic
0.45
D
MetaRNN
Pathogenic
0.94
D;D;D
MetaSVM
Uncertain
-0.18
T
MutationAssessor
Uncertain
2.1
M;.;.
PrimateAI
Uncertain
0.73
T
PROVEAN
Uncertain
-3.1
D;D;D
REVEL
Uncertain
0.59
Sift
Pathogenic
0.0
D;D;D
Sift4G
Uncertain
0.011
D;D;D
Polyphen
1.0
D;B;.
Vest4
0.98
MutPred
0.83
Loss of helix (P = 0.2022);.;.;
MVP
0.92
MPC
1.2
ClinPred
1.0
D
GERP RS
4.6
Varity_R
0.56
gMVP
0.87

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: rs1555535407; hg19: chr17-29670055; API