17-31233091-C-T

Variant names:

• chr17-31233091-C-T
• rs1555615039
• NM_001042492.3:c.3586C>T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP2 PP5_Very_Strong

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 Likely pathogenic (★★). 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: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• 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 Pathogenic. Variant got 15 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 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 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.
• PP5: Variant 17-31233091-C-T is Pathogenic according to our data. Variant chr17-31233091-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1036158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31233091-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.3586C>T	p.Leu1196Phe	missense_variant	Exon 27 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.3586C>T	p.Leu1196Phe	missense_variant	Exon 27 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.3586C>T	p.Leu1196Phe	missense_variant	Exon 27 of 58	1	NM_001042492.3	ENSP00000351015.4

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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:2

May 15, 2023

Department Of Biochemistry, Hamamatsu University School Of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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). -

Sep 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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: 1036158). 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). 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). -

not provided Pathogenic:2

Jul 20, 2021

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NF1: PM1, PM2, PM5, PS4:Moderate, PP4 -

Neurofibromatosis, type 1;C0349639:Juvenile myelomonocytic leukemia;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome Pathogenic:1

Jan 09, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Nov 05, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 variant was reported in multiple individuals with features consistent with Neurofibromatosis type 1 (Ben-Shachar S et al. Eur. J. Hum. Genet., 2013 May;21:535-9; Calì F et al. Eur J Med Genet, 2017 Feb;60:93-99; Kang E et al. J Hum Genet, 2020 Jan;65:79-89; Ambry internal data). This variant was also 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). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	0.28	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;.
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;