rs786203307

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_001042492.3(NF1):c.55G>A(p.Glu19Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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. E19A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NF1
NM_001042492.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.47

Publications

7 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 links:

MIR4733HG (HGNC:55332): (MIR4733 host gene)

MIR4733HG links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 39 uncertain in NM_001042492.3

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2558263).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
NF1	NM_001042492.3 link	c.55G>A	p.Glu19Lys	missense_variant	Exon 1 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4 link	c.55G>A	p.Glu19Lys	missense_variant	Exon 1 of 57		NP_000258.1
NF1	NM_001128147.3 link	c.55G>A	p.Glu19Lys	missense_variant	Exon 1 of 15		NP_001121619.1
MIR4733HG	NR_186435.1 link	n.127C>T		non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 link	c.55G>A	p.Glu19Lys	missense_variant	Exon 1 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1387828

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

684834

African (AFR)

AF:

0.00

AC:

AN:

31586

American (AMR)

AF:

0.00

AC:

AN:

35656

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25110

East Asian (EAS)

AF:

0.00

AC:

AN:

35940

South Asian (SAS)

AF:

0.00

AC:

AN:

79104

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39946

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4206

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078522

Other (OTH)

AF:

0.00

AC:

AN:

57758

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurofibromatosis, type 1

Uncertain:1

Nov 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 19 of the NF1 protein (p.Glu19Lys). This variant is not present in population databases (gnomAD no frequency). 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: 582267). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NF1 protein function. 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.

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Uncertain:1

Dec 05, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.E19K variant (also known as c.55G>A), located in coding exon 1 of the NF1 gene, results from a G to A substitution at nucleotide position 55. The glutamic acid at codon 19 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0

.;D;.;.

Eigen

Benign

0.050

Eigen_PC

Benign

0.065

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Pathogenic

0.53

MetaRNN

Benign

0.26

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;M;M;M

PhyloP100

5.5

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

0.0

.;N;N;N

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;T;T;T

Sift4G

Pathogenic

0.0

.;D;D;D

Vest4

0.0

ClinPred

0.93

GERP RS

2.7

PromoterAI

0.059

Neutral

(source)

Varity_R

0.35

gMVP

0.49

Mutation Taster

=59/41

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over