rs1060500344

Positions:

• chr17-31338138-A-G
• chr17-31338138-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP5

The NM_001042492.3(NF1):​c.6818A>G​(p.Lys2273Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:2
• Conservation: PhyloP100: 8.73

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NF1. . Gene score misZ 6.5427 (greater than the threshold 3.09). Trascript score misZ 8.4054 (greater than threshold 3.09). GenCC has associacion of gene with neurofibromatosis, familial spinal, hereditary pheochromocytoma-paraganglioma, neurofibromatosis type 1, Watson syndrome, neurofibromatosis-Noonan syndrome, Moyamoya disease, familial ovarian cancer.
• PP5: Variant 17-31338138-A-G is Pathogenic according to our data. Variant chr17-31338138-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 428947.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=3}. Variant chr17-31338138-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.6818A>G	p.Lys2273Arg	missense_variant, splice_region_variant	45/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.6755A>G	p.Lys2252Arg	missense_variant, splice_region_variant	44/57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.6818A>G	p.Lys2273Arg	missense_variant, splice_region_variant	45/58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 14, 2022	This missense change has been observed in individual(s) with neurofibromatosis type 1 (PMID: 31766501; Invitae). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this missense change is associated with altered splicing resulting in an unknown protein product impact (PMID: 31766501). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 428947). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 2252 of the NF1 protein (p.Lys2252Arg). -
Pathogenic, no assertion criteria provided	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Dec 10, 2018	The observed missense variant NM_001042492.2: c.6818A>G(p.Lys2273Arg) in exon-45 of the NF1 gene is present in a hot-spot region consisting of 20 missense/ in-frame variants. The variant is not observed on the gnomAD and 1000 genomes databases. In silico evidence suggests damaging effect by REVEL, dbsvSNV and FATHMM-MKL. The variant has previously been reported in ClinVar as pathogenic/ likely pathogenic (RCV000735821). In summary, the aforementioned variant meets our criteria to be classified as pathogenic based upon absence from controls, literature evidence and in silico evidence. -
Pathogenic, criteria provided, single submitter	clinical testing	NHS Central & South Genomic Laboratory Hub	Jul 01, 2024	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2024

The p.K2252R variant (also known as c.6755A>G), located in coding exon 44 of the NF1 gene, results from an A to G substitution at nucleotide position 6755. This variant was reported in multiple individuals with features consistent with neurofibromatosis type 1 (van Minkelen R et al. Clin Genet, 2014 Apr;85:318-27; Zhang J et al. Sci Rep, 2015 Jun;5:11291; Melloni G et al. Cancers (Basel), 2019 Nov;11:; Zhao S et al. J Med Genet, 2021 Jan;58:41-47; Ambry internal data). The lysine at codon 2252 is replaced by arginine, 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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 21, 2024

Identified in patients with clinical features of neurofibromatosis type 1 in published literature (PMID: 29673180, 31766501, 32575496, 32381727); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis supports that this variant has a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 23656349, 31766501, 32381727, 29673180, 32575496) -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, flagged submission

clinical testing

Ambry Genetics

Jul 09, 2014

The p.K2273R variant (also known as c.6818A>G), located in coding exon 45 of the NF1 gene, results from an A to G substitution at nucleotide position 6818. The lysine at codon 2273 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.<span data-redactor="verified" style="background-color: initial;">To date, this alteration has been detected with an allele frequency of approximately 0.02% (greater than 5000 alleles tested) in our clinical cohort (includes this individual). This variant is located 2 nucleotides away from the end of exon 45 and is predicted to weaken the adjacent donor splice site efficiency, however direct evidence is unavailable.<span data-redactor="verified" style="background-color: initial;">This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.<span data-redactor="verified" style="background-color: initial;">Since supporting evidence is limited at this time, the clinical significance of<span data-redactor="verified" style="background-color: initial;">p.K2273R<strong style="background-color: initial;"><span data-redactor="verified" style="background-color: initial;">remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;.;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.5	L;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Pathogenic	0.68
Sift	Benign	0.28	T;T;T
Sift4G	Benign	0.38	T;T;T
Polyphen		0.041	B;D;.
Vest4		0.82
MutPred		0.33		Loss of ubiquitination at K2273 (P = 0.0297);.;.;
MVP		0.81
MPC		2.1
ClinPred		0.95	D
GERP RS		5.4
Varity_R		0.24
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.85		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060500344; hg19: chr17-29665156; COSMIC: COSV100648642; COSMIC: COSV100648642;