rs749949219

Variant names:

• chr17-31182638-C-A
• rs749949219
• NM_001042492.3:c.861C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-31182638-C-A
• chr17-31182638-C-G
• chr17-31182638-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001042492.3(NF1):​c.861C>A​(p.Asp287Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. D287V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.107
• 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), 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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.055407196).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.861C>A	p.Asp287Glu	missense_variant	Exon 8 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.861C>A	p.Asp287Glu	missense_variant	Exon 8 of 57		NP_000258.1
NF1	NM_001128147.3	c.861C>A	p.Asp287Glu	missense_variant	Exon 8 of 15		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.861C>A	p.Asp287Glu	missense_variant	Exon 8 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Uncertain:1

May 27, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D287E variant (also known as c.861C>A), located in coding exon 8 of the NF1 gene, results from a C to A substitution at nucleotide position 861. The aspartic acid at codon 287 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is conserved. 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	Benign	0.14
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	6.1
DANN	Benign	0.76
DEOGEN2	Uncertain	0.47	.;T;.;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.84	T;T;T;T;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.055	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;N;N;N;.
PhyloP100		0.11
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.86	.;N;N;N;.
REVEL	Benign	0.095
Sift	Benign	0.52	.;T;T;T;.
Sift4G	Benign	1.0	.;T;T;T;.
Polyphen		0.0030	B;B;B;.;.
Vest4		0.25, 0.22, 0.26
MutPred		0.19		Gain of methylation at K286 (P = 0.0694);Gain of methylation at K286 (P = 0.0694);Gain of methylation at K286 (P = 0.0694);Gain of methylation at K286 (P = 0.0694);.;
MVP		0.36
MPC		0.64
ClinPred		0.071	T
GERP RS		1.8
Varity_R		0.041
gMVP		0.13
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs749949219; hg19: chr17-29509656;