chr17-31233091-C-T

Position:

• chr17-31233091-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP2 PP5

The NM_001042492.3(NF1):​c.3586C>T​(p.Leu1196Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,172 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L1196R) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 2.33

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_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 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 chr17-31233092-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 17-31233091-C-T is Pathogenic according to our data. Variant chr17-31233091-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1036158.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=3, Pathogenic=1}. Variant chr17-31233091-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.3586C>T	p.Leu1196Phe	missense_variant	27/58	ENST00000358273.9
NF1	NM_000267.3	c.3586C>T	p.Leu1196Phe	missense_variant	27/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.3586C>T	p.Leu1196Phe	missense_variant	27/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74336

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 25, 2023	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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 1196 of the NF1 protein (p.Leu1196Phe). This missense change has been observed in individuals with clinical features of NF1-related conditions, neurofibromatosis type 1, and/or neurofibromatosis-Noonan syndrome (PMID: 17103458, 22664660, 23047742, 27838393, 31776437). ClinVar contains an entry for this variant (Variation ID: 1036158). -
Pathogenic, criteria provided, single submitter	research	Department Of Biochemistry, Hamamatsu University School Of Medicine	May 15, 2023	Sanger sequencing confirmed that this variant was de novo . This variant was absent from the public databases, including the Genome Aggregation Database (gnomAD) v3.1.2 , ToMMo 38KJPN Allele Frequency Panel , and 82 in-house Japanese exome control data. This variant was evolutionarily highly conserved and predicted to be deleterious by multiple pathogenicity prediction tools. Based on American College of Medical Genetics and Genomics standards and guidelines, the c.3586C>T, p.(Leu1196Phe) in NF1 was classified as pathogenic (PS1, PS2, PM2, PP3). -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2021	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23047742, 27838393, 34039477, 17103458, 27535533, 31776437, 22664660) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	NF1: PM1, PM2, PM5, PS4:Moderate, PP4 -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2017

The p.L1196F variant (also known as c.3586C>T), located in coding exon 27 of the NF1 gene, results from a C to T substitution at nucleotide position 3586. The leucine at codon 1196 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. This alteration was detected as a de novo occurrence in an individual with a clinical diagnosis of Noonan syndrome who had cafe au lait spots, but did not meet NIH diagnostic criteria for Neurofibromatosis type 1 (NF1) (Croonen EA et al. Clin. Dysmorphol., 2012 Oct;21:212-4). In another study, this alteration was detected in an individual with either a suspected or confirmed diagnosis of NF1 (Calì F et al. Eur J Med Genet, 2017 Feb;60:93-99). In addition, internal structural analysis showed that the L1196F alteration does not destabilize protein structure (Scheffzek K et al. EMBO J., 1998 Aug;17:4313-27; Welti S et al. Hum. Mutat., 2011 Feb;32:191-7). A different alteration, located at the same protein position, p.L1196V, was detected in an individual who may have fulfilled NF1 NIH diagnostic criteria (Bianchessi D et al. Mol Genet Genomic Med, 2015 Nov;3:513-25). An additional different alteration, located at the same protein position, p.L1196R, was identified in two individuals who did not meet NF1 NIH diagnostic criteria and was shown to have no impact on protein folding (Mattocks C et al. J. Med. Genet., 2004 Apr;41:e48; Hüffmeier U et al. Am. J. Med. Genet. A, 2006 Dec;140:2749-56; Kiel C et al. Mol. Syst. Biol., 2014 May;10:727). The p.L1196F alteration is predicted to be possibly damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of the p.L1196F alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;.;D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Pathogenic	3.2	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Benign	0.25
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.63	P;D;.
Vest4		0.81
MutPred		0.43		Gain of helix (P = 0.027);Gain of helix (P = 0.027);.;
MVP		0.82
MPC		1.8
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.47
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555615039; hg19: chr17-29560109; COSMIC: COSV62222170;