rs1060500262

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_001042492.3(NF1):c.3336C>A(p.Asn1112Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,780 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 Uncertain significance (★★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

NF1
NM_001042492.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.12

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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=0.36253908).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3 link	c.3336C>A	p.Asn1112Lys	missense_variant	Exon 26 of 58	ENST00000358273.9	NP_001035957.1	P21359-1
NF1	NM_000267.3 link	c.3336C>A	p.Asn1112Lys	missense_variant	Exon 26 of 57		NP_000258.1	P21359-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 link	c.3336C>A	p.Asn1112Lys	missense_variant	Exon 26 of 58	1	NM_001042492.3	ENSP00000351015.4		P21359-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461780

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

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

Jul 29, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an NF1-related disease. This sequence change replaces asparagine with lysine at codon 1112 of the NF1 protein (p.Asn1112Lys). The asparagine residue is moderately conserved and there is a moderate physicochemical difference between asparagine and lysine. -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Uncertain:1

Nov 23, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.N1112K variant (also known as c.3336C>A), located in coding exon 26 of the NF1 gene, results from a C to A substitution at nucleotide position 3336. The asparagine at codon 1112 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. 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

0.97

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

D;.;T

Eigen

Benign

-0.042

Eigen_PC

Benign

0.056

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Pathogenic

0.47

MetaRNN

Benign

0.36

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

L;L;.

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-4.0

D;D;D

REVEL

Benign

0.094

Sift

Benign

0.078

T;T;T

Sift4G

Benign

0.28

T;T;T

Polyphen

0.048

B;D;.

Vest4

0.91

MutPred

0.50

Gain of ubiquitination at N1112 (P = 0.0238);Gain of ubiquitination at N1112 (P = 0.0238);.;

MVP

0.43

MPC

1.8

ClinPred

0.97

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.49

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over