rs199474785

Positions:

• chr17-31229145-C-T

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.2530C>T​(p.Leu844Phe) 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 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. L844H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 2.47

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 helix (size 14) in uniprot entity NF1_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) 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 chr17-31229146-T-A is described in Lovd as [Pathogenic].
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881
• PP5: Variant 17-31229145-C-T is Pathogenic according to our data. Variant chr17-31229145-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31229145-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.2530C>T	p.Leu844Phe	missense_variant	21/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.2530C>T	p.Leu844Phe	missense_variant	21/57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.2530C>T	p.Leu844Phe	missense_variant	21/58	1	NM_001042492.3	ENSP00000351015	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 18, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 04, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu844 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9150739, 15060124, 15948193, 29290338). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 68321). This missense change has been observed in individuals with neurofibromatosis type 1 (PMID: 10980545, 15060124, 27322474, 29290338). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 844 of the NF1 protein (p.Leu844Phe). -
Pathogenic, criteria provided, single submitter	clinical testing	UAB Medical Genomics Laboratory, UAB Medicine	Jun 05, 2019	- -

not provided Pathogenic:2 Other:1

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24803665, 10980545, 27322474, 26076063, 15060124, 26214590, 10712197, 29290338, 32619305, 2121369, 25486365, 35353986) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 08, 2023	PP2, PP4, PM2, PS2_very_strong, PS4_moderate -

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 21, 2020

The p.L844F pathogenic mutation (also known as c.2530C>T), located in coding exon 21 of the NF1 gene, results from a C to T substitution at nucleotide position 2530. The leucine at codon 844 is replaced by phenylalanine, an amino acid with highly similar properties. This variant occurs in a hotspot for missense mutations within NF1 and has been detected in multiple individuals with a clinical or suspected diagnosis of neurofibromatosis type 1 (NF1) (Girodon-Boulandet E et al. Hum. Mutat., 2000 Sep;16:274-5; Mattocks C et al. J Med Genet, 2004 Apr;41:e48; Evans DG et al. EBioMedicine, 2016 May;7:212-20; Koczkowska M et al. Am. J. Hum. Genet., 2018 01;102:69-87). In a large cohort study, the variant was detected de novo in three individuals with NF1 and co-segregated with disease in one family (Koczkowska M et al. Am. J. Hum. Genet., 2018 01;102:69-87). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2016

The p.L844F variant (also known as c.2530C>T), located in coding exon 21 of the NF1 gene, results from a C to T substitution at nucleotide position 2530. The leucine at codon 844 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with a clinical diagnosis of NF1 (Mattocks C et al.J. Med. Genet. 2004 Apr; 41(4):e48;Girodon-BoulandetE et al.Hum.Mutat. 2000 Sep;16(3):274-5). Based on in silico analyses combining3D structure, energy calculations, and conservation, this alteration was categorized as likely disease-causing(Kiel C et al.Mol.Syst.Biol. 2014;10():727).This variant was previously reported in the SNPDatabase as rs199474785;however, it was not reported in population-based cohorts in the NHLBI Exome Sequencing Project (ESP) or 1000 Genomes Project databases. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 110000alleles tested) in our clinical cohort.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	0.99
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;.;D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.9	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.94
MutPred		0.84		Gain of catalytic residue at L844 (P = 0.0378);Gain of catalytic residue at L844 (P = 0.0378);.;
MVP		0.80
MPC		1.8
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.74
gMVP		0.80

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: rs199474785; hg19: chr17-29556163; COSMIC: COSV62197747; COSMIC: COSV62197747;