17-31156049-C-G

Variant names:

• chr17-31156049-C-G
• rs1060503913
• NM_001042492.3:c.127C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_001042492.3(NF1):​c.127C>G​(p.Leu43Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L43P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 3.02
• 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_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 27 uncertain in NM_001042492.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-31156050-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 457527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 17-31156049-C-G is Pathogenic according to our data. Variant chr17-31156049-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3404578.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.127C>G	p.Leu43Val	missense_variant	Exon 2 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.127C>G	p.Leu43Val	missense_variant	Exon 2 of 57		NP_000258.1
NF1	NM_001128147.3	c.127C>G	p.Leu43Val	missense_variant	Exon 2 of 15		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.127C>G	p.Leu43Val	missense_variant	Exon 2 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

May 05, 2025

Unidad de Genética Molecular HGU Elche, Hospital General Universitario de Elche

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM5 strong; PM1 moderate; PM2 supporting -

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

Oct 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L43V variant (also known as c.127C>G), located in coding exon 2 of the NF1 gene, results from a C to G substitution at nucleotide position 127. The leucine at codon 43 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	23
DANN	Benign	0.93
DEOGEN2	Uncertain	0.72	.;D;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Uncertain	0.55	D;D;D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.5	M;M;M;M
PhyloP100		3.0
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.9	.;N;N;N
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	.;D;D;D
Sift4G	Uncertain	0.0030	.;D;D;D
Polyphen		0.97	D;D;D;.
Vest4		0.85, 0.84, 0.85
MutPred		0.36		Loss of catalytic residue at L43 (P = 0.0059);Loss of catalytic residue at L43 (P = 0.0059);Loss of catalytic residue at L43 (P = 0.0059);Loss of catalytic residue at L43 (P = 0.0059);
MVP		0.75
MPC		1.7
ClinPred		0.94	D
GERP RS		4.0
Varity_R		0.51
gMVP		0.68
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1060503913; hg19: chr17-29483067; COSMIC: COSV62200385; COSMIC: COSV62200385;