rs199474746

chr17-31227536-C-Achr17-31227536-C-G

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001042492.3(NF1):c.2339C>A(p.Thr780Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T780A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 7.38

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 Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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 chr17-31227535-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1216533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, NF1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84
• PP5: Variant 17-31227536-C-A is Pathogenic according to our data. Variant chr17-31227536-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31227536-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.2339C>A	p.Thr780Lys	missense_variant	20/58	ENST00000358273.9
NF1	NM_000267.3	c.2339C>A	p.Thr780Lys	missense_variant	20/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.2339C>A	p.Thr780Lys	missense_variant	20/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251338 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135842

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 17, 2023	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NF1 protein function. ClinVar contains an entry for this variant (Variation ID: 68316). This missense change has been observed in individual(s) with Neurofibromatosis type 1 (PMID: 1071297, 11735023, 12552569, 15146469, 16944272, 26478990). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs199474746, gnomAD 0.007%). This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 780 of the NF1 protein (p.Thr780Lys). -

not provided Pathogenic:1 Other:1

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 12, 2017	The NF1 c.2339C>A; p.Thr780Lys variant (rs199474746) has been reported in multiple unrelated individuals with NF1, and was found de novo in at least one individual (De Luca 2003, De Luca 2004, Esposito 2015, Fahsold 2000, Han 2001). Additionally, two other alterations at this codon (p.Thr780Arg, p.Thr780Pro) have been reported in individuals with NF1 (Griffiths 2007, Laycock-van Spyk 2011). The p.Thr780Lys variant is reported as pathogenic in ClinVar (Variation ID: 68316), and is observed in the general population at a low overall allele frequency of 0.0004% (1/246132 alleles) in the Genome Aggregation Database. The threonine at codon 780 is highly conserved and computational algorithms (SIFT, PolyPhen2, MutationTaster, Align GVGD) predict this variant to be damaging to the protein. Taken together, the p.Thr780Lys variant is considered pathogenic. REFERENCES De Luca A et al. NF1 gene analysis based on DHPLC. Hum Mutat. 2003 Feb;21(2):171-2. De Luca A et al. Novel and recurrent mutations in the NF1 gene in Italian patients with neurofibromatosis type 1. Hum Mutat. 2004 Jun;23(6):629. Esposito T et al. A novel diagnostic method to detect truncated neurofibromin in neurofibromatosis 1. J Neurochem. 2015 Dec;135(6):1123-8. Fahsold R et al. Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. Am J Hum Genet. 2000 Mar;66(3):790-818. Griffiths S et al. Molecular diagnosis of neurofibromatosis type 1: 2 years experience. Fam Cancer. 2007;6(1):21-34. Han SS et al. Evaluation of denaturing high performance liquid chromatography (DHPLC) for the mutational analysis of the neurofibromatosis type 1 ( NF1) gene. Hum Genet. 2001 Nov;109(5):487-97. Laycock-van Spyk S et al. Neurofibromatosis type 1-associated tumours: their somatic mutational spectrum and pathogenesis. Hum Genomics. 2011 Oct;5(6):623-90. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 10, 2017

The p.T780K variant (also known as c.2339C>A), located in coding exon 20 of the NF1 gene, results from a C to A substitution at nucleotide position 2339. The threonine at codon 780 is replaced by lysine, an amino acid with some similar properties. This alteration has been reported multiple times in the literature in individuals who meet NIH neurofibromatosis type 1 diagnostic criteria (Evans DG et al. EBioMedicine, 2016 May;7:212-20; Fahsold R et al. Am. J. Hum. Genet., 2000 Mar;66:790-818; De Luca A et al. Hum. Mutat., 2004 Jun;23:629; Esposito T et al. J. Neurochem., 2015 Dec;135:1123-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;.;T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.3	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.6	D;D;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.99
MutPred		0.45		Gain of ubiquitination at T780 (P = 0.0185);Gain of ubiquitination at T780 (P = 0.0185);.;
MVP		0.89
MPC		1.9
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.83
gMVP		0.91

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: rs199474746; hg19: chr17-29554554;