17-31352265-A-G

Variant names:

• chr17-31352265-A-G
• rs864622249
• NM_001042492.3:c.7466A>G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Strong BP6 BS2_Supporting

The NM_001042492.3(NF1):​c.7466A>G​(p.Lys2489Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000753 in 1,461,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 4.04

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant in the NF1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 399 curated pathogenic missense variants (we use a threshold of 10). The gene has 143 curated benign missense variants. Gene score misZ: 6.5427 (above the threshold of 3.09). Trascript score misZ: 8.4054 (above the threshold of 3.09). GenCC associations: The gene is linked to neurofibromatosis, familial spinal, hereditary pheochromocytoma-paraganglioma, neurofibromatosis type 1, Watson syndrome, neurofibromatosis-Noonan syndrome, Moyamoya disease, familial ovarian cancer.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0662196).
• BP6: Variant 17-31352265-A-G is Benign according to our data. Variant chr17-31352265-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 219783.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=4}.
• BS2: High AC in GnomAdExome4 at 11 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.7466A>G	p.Lys2489Arg	missense_variant	Exon 51 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.7403A>G	p.Lys2468Arg	missense_variant	Exon 50 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.7466A>G	p.Lys2489Arg	missense_variant	Exon 51 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461744 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727186

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000579 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurofibromatosis, type 1 Uncertain:1 Benign:1

Mar 15, 2022

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Juvenile myelomonocytic leukemia Uncertain:1

Nov 20, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Jul 11, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25486365) -

Hereditary cancer-predisposing syndrome Uncertain:1

Jul 01, 2015

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K2489R variant (also known as c.7466A>G), located in coding exon 51 of the NF1 gene, results from an A to G substitution at nucleotide position 7466. The lysine at codon 2489 is replaced by arginine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 55000 alleles tested) in our clinical cohort.This amino acid position is well conserved in most vertebrate species, however arginine is the reference amino acid in multiple fishspecies. 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 p.K2489R remains unclear. -

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

Oct 24, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T;.;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.055
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.066	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.7	N;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.16	N;N;N
REVEL	Benign	0.085
Sift	Benign	0.40	T;T;T
Sift4G	Benign	0.83	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.24
MutPred		0.19		Loss of ubiquitination at K2489 (P = 0.0081);.;.;
MVP		0.21
MPC		0.42
ClinPred		0.71	D
GERP RS		6.1
Varity_R		0.063
gMVP		0.13

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

Publications

LitVar

Other links and lift over

dbSNP: rs864622249; hg19: chr17-29679283;