NM_001042492.3:c.266C>A

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_001042492.3(NF1):c.266C>A(p.Thr89Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. T89A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

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:5

Conservation

PhyloP100: 7.28

Publications

0 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 Gene-Disease associations (from GenCC):

neurofibromatosis type 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
neurofibromatosis-Noonan syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
Moyamoya disease
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
hereditary pheochromocytoma-paraganglioma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

NF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 28 uncertain in NM_001042492.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.852

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
NF1	NM_001042492.3 link	c.266C>A	p.Thr89Lys	missense_variant	Exon 3 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4 link	c.266C>A	p.Thr89Lys	missense_variant	Exon 3 of 57		NP_000258.1
NF1	NM_001128147.3 link	c.266C>A	p.Thr89Lys	missense_variant	Exon 3 of 15		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 link	c.266C>A	p.Thr89Lys	missense_variant	Exon 3 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:

1456076

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724796

African (AFR)

AF:

0.00

AC:

AN:

33372

American (AMR)

AF:

0.00

AC:

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26076

East Asian (EAS)

AF:

0.00

AC:

AN:

39488

South Asian (SAS)

AF:

0.00

AC:

AN:

86134

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53296

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107104

Other (OTH)

AF:

0.00

AC:

AN:

60176

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurofibromatosis, type 1

Uncertain:3

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 89 of the NF1 protein (p.Thr89Lys). 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: 547565). 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 expected to disrupt NF1 protein function with a positive 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.

Mar 15, 2022

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Uncertain:1

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NF1: PM1, PM2, PP3

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Uncertain:1

Oct 31, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.T89K variant (also known as c.266C>A), located in coding exon 3 of the NF1 gene, results from a C to A substitution at nucleotide position 266. The threonine at codon 89 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 deleterious 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

1.0

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.0

.;D;.;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

D;D;D;D

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.85

D;D;D;D

MetaSVM

Uncertain

0.49

MutationAssessor

Uncertain

2.3

M;M;M;M

PhyloP100

7.3

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

0.0

.;D;D;D

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;D;D;D

Sift4G

Pathogenic

0.0

.;D;D;D

Vest4

0.0

ClinPred

0.99

GERP RS

5.1

PromoterAI

-0.013

Neutral

(source)

Varity_R

0.75

gMVP

0.89

Mutation Taster

=9/91

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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