chr17-31182616-T-A

Variant names:

• chr17-31182616-T-A
• rs1555608976
• NM_001042492.3:c.839T>A
• NF1 p.Ile280Lys

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+3 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

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

The NM_001042492.3(NF1):c.839T>A (p.Ile280Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.14
• Publications: 0 publications found

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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 3 points.

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

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	NF1 NM_001042492.3	MANE Select	c.839T>A p.Ile280Lys	missense	Exon 8 of 58	Prot: NP_001035957.1 UniProt:
	NF1 NM_000267.4		c.839T>A p.Ile280Lys	missense	Exon 8 of 57	Prot: NP_000258.1 UniProt:
	NF1 NM_001128147.3		c.839T>A p.Ile280Lys	missense	Exon 8 of 15	Prot: NP_001121619.1 UniProt:

NF1 NM_001042492.3

MANE Select

HGVSc / HGVSpc.839T>Ap.Ile280Lys

Exon rankExon 8 of 58

missense

Prot: NP_001035957.1UniProt: P21359-1

NF1 NM_000267.4

HGVSc / HGVSpc.839T>Ap.Ile280Lys

Exon rankExon 8 of 57

missense

Prot: NP_000258.1UniProt: P21359-2

NF1 NM_001128147.3

HGVSc / HGVSpc.839T>Ap.Ile280Lys

Exon rankExon 8 of 15

missense

Prot: NP_001121619.1UniProt: P21359-5

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	NF1 ENST00000358273.9	TSL:1MANE Select	c.839T>A p.Ile280Lys	missense	Exon 8 of 58	Prot: ENSP00000351015.4 UniProt:
	NF1 ENST00000356175.7	TSL:1	c.839T>A p.Ile280Lys	missense	Exon 8 of 57	Prot: ENSP00000348498.3 UniProt:
	NF1 ENST00000431387.8	TSL:1	c.839T>A p.Ile280Lys	missense	Exon 8 of 15	Prot: ENSP00000412921.4 UniProt:

NF1 ENST00000358273.9

TSL:1MANE Select

HGVSc / HGVSpc.839T>Ap.Ile280Lys

Exon rankExon 8 of 58

missense

Prot: ENSP00000351015.4UniProt: P21359-1

NF1 ENST00000356175.7

TSL:1

HGVSc / HGVSpc.839T>Ap.Ile280Lys

Exon rankExon 8 of 57

missense

Prot: ENSP00000348498.3UniProt: P21359-2

NF1 ENST00000431387.8

TSL:1

HGVSc / HGVSpc.839T>Ap.Ile280Lys

Exon rankExon 8 of 15

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	26
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Pathogenic	0.84	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
FuncVEP CTI	Pathogenic	0.57
GPN-Star LLR	N/A	-9.6
GPN-Star score	N/A	9.6
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.065	T
Mutation Taster	N/A	39/61	disease causing
MutationAssessor	Uncertain	2.1	M
PhyloP100	Uncertain	7.1
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0060	D
Varity_R	N/A	0.53
VESM-3B	Benign	-12

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

Other links and lift over

dbSNP: rs1555608976;

hg19: chr17-29509634;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar