Genetic Variant NF1:p.Ile280Lys (chr17-31182616-TA-AG) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is The variant received 3 classification points (ACMG Germline Pathogenicity v2019). PM1_SupportingPM2

The NM_001042492.3(NF1):c.839_840delTAinsAG (p.Ile280Lys) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.I280T: Uncertain_significance (ClinVar VariationId 517245, 1 star)

Frequency

Genomes: not found (cov: 32)

Consequence

NF1
NM_001042492.3 missense

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.14

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), PanelApp Australia, ClinGen, G2P, Genomics England PanelApp
neurofibromatosis-Noonan syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
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: Unknown Classification: NO_KNOWN Submitted by: ClinGen

NF1 links:

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new If you want to explore the variant's impact on the transcript NM_001042492.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 3 points.

Show applied only (2)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		Missense neighbourhood moderate hotspot (≥2 P/LP within ±8 AA, OR ≥ 2 vs. background) — PM1 supporting; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 3 pathogenic, 4 benign (OR vs. background: 3.9).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00122) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001042492.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
NF1 NM_001042492.3	MANE Select	c.839_840delTAinsAG p.Ile280Lys	missense	N/A	Prot: NP_001035957.1 UniProt: P21359-1
NF1 NM_000267.4		c.839_840delTAinsAG p.Ile280Lys	missense	N/A	Prot: NP_000258.1 UniProt: P21359-2
NF1 NM_001128147.3		c.839_840delTAinsAG p.Ile280Lys	missense	N/A	Prot: NP_001121619.1 UniProt: P21359-5

NF1 NM_001042492.3

MANE Select

HGVSc / HGVSpc.839_840delTAinsAGp.Ile280Lys

Exon rankN/A

missense

Prot: NP_001035957.1UniProt: P21359-1

NF1 NM_000267.4

HGVSc / HGVSpc.839_840delTAinsAGp.Ile280Lys

Exon rankN/A

missense

Prot: NP_000258.1UniProt: P21359-2

NF1 NM_001128147.3

HGVSc / HGVSpc.839_840delTAinsAGp.Ile280Lys

Exon rankN/A

missense

Prot: NP_001121619.1UniProt: P21359-5

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
NF1 ENST00000358273.9	TSL:1MANE Select	c.839_840delTAinsAG p.Ile280Lys	missense	N/A	Prot: ENSP00000351015.4 UniProt: P21359-1
NF1 ENST00000356175.7	TSL:1	c.839_840delTAinsAG p.Ile280Lys	missense	N/A	Prot: ENSP00000348498.3 UniProt: P21359-2
NF1 ENST00000431387.8	TSL:1	c.839_840delTAinsAG p.Ile280Lys	missense	N/A	Prot: ENSP00000412921.4 UniProt: P21359-5

NF1 ENST00000358273.9

TSL:1MANE Select

HGVSc / HGVSpc.839_840delTAinsAGp.Ile280Lys

Exon rankN/A

missense

Prot: ENSP00000351015.4UniProt: P21359-1

NF1 ENST00000356175.7

TSL:1

HGVSc / HGVSpc.839_840delTAinsAGp.Ile280Lys

Exon rankN/A

missense

Prot: ENSP00000348498.3UniProt: P21359-2

NF1 ENST00000431387.8

TSL:1

HGVSc / HGVSpc.839_840delTAinsAGp.Ile280Lys

Exon rankN/A

missense

Prot: ENSP00000412921.4UniProt: P21359-5

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	7.1

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence