chr17-31265335-C-T

Variant names:

• chr17-31265335-C-T
• rs1060500316
• NM_001042492.3:c.4831C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1 PM5 PP3_Moderate BS2_Supporting

The NM_001042492.3(NF1):​c.4831C>T​(p.Arg1611Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000413 in 1,453,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R1611Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:8 O:1
• Conservation: PhyloP100: 3.45
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• neurofibromatosis type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
• Moyamoya disease

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_001042492.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-31265336-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 2045116.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884
• BS2: High AC in GnomAdExome4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.4831C>T	p.Arg1611Trp	missense_variant	Exon 36 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.4768C>T	p.Arg1590Trp	missense_variant	Exon 35 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.4831C>T	p.Arg1611Trp	missense_variant	Exon 36 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250500 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000413 AC: 6 AN: 1453770 Hom.: 0 Cov.: 28 AF XY: 0.00000276 AC XY: 2 AN XY: 723852

African (AFR) AF: 0.00 AC: 0 AN: 33292

American (AMR) AF: 0.00 AC: 0 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39518

South Asian (SAS) AF: 0.00 AC: 0 AN: 86110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1105094

Other (OTH) AF: 0.0000333 AC: 2 AN: 60056

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:8 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:2 Uncertain:1 Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Uncertain significance and reported on 02-10-2021 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1590 of the NF1 protein (p.Arg1590Trp). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of neurofibromatosis type 1 (PMID: 9298829, 27322474, 29673180, 32575496). ClinVar contains an entry for this variant (Variation ID: 404515). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt NF1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects NF1 function (PMID: 21089070). This variant disrupts the p.Arg1590 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Mar 11, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NF1 c.4768C>T (p.Arg1590Trp) results in a non-conservative amino acid change located in the CRAL-TRIO lipid binding domain (IPR001251) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250500 control chromosomes. c.4768C>T has been reported in the heterozygous state in the literature and internally in multiple individuals affected with Neurofibromatosis Type 1, NF1-Noonan spectrum conditions, isolated cafe au lait macules or breast cancer (Upadhyaya_1997,Giugliano_2019,Dorling_2021, Stella_2018, Bianchessi_2020, Evans_2016, Labcorp Genetics (formerly Invitae)). It has also been reported in control cohorts and clinically unaffected family members (Okawa_2023, Dorling_2021, Evans_2016, Bianchessi_2020), suggesting incomplete penetrance or variable expressivity. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in about 20% of NF1 expression in E. coli (Welti_2010). Additionally, one missense variant at the Arg1590 residue has been reported in ClinVar (NM_000267.3:c.4769G>T p.Arg1590Leu), suggesting that this codon might be functionally important. The following publications have been ascertained in the context of this evaluation (PMID: 33471991, 31370276, 36243179, 9298829, 21089070, 29673180, 32575496, 27322474). ClinVar contains an entry for this variant (Variation ID: 404515). Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 15, 2022

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:4

Sep 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 11, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 11, 2020

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 12, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with features of neurofibromatosis type 1, several of whom did not meet NIH criteria (PMID: 9298829, 27322474, 29471550, 29673180, 31370276, 32575496); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in clinically unaffected adult relatives of individuals with features of neurofibromatosis type 1 referred for genetic testing at GeneDx and in published literature (PMID: 32575496, 27322474); This variant is associated with the following publications: (PMID: 32680567, 21089070, 9298829, 24803665, 27322474, 16405917, 29471550, 31370276, 32575496, 29673180, 35885913, 36243179) -

NF1-related disorder Uncertain:1

Sep 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NF1 c.4831C>T variant is predicted to result in the amino acid substitution p.Arg1611Trp. This variant is also referred to as p.Arg1590Trp in an alternate transcript (NM_000267.3). This variant has been reported in individuals with features of neurofibromatosis type 1 (Upadhyaya et al. 1997. PubMed ID: 9298829; Giugliano et al. 2019. PubMed ID: 31370276; Stella A et al. 2018. PubMed ID: 29673180). However, the variant was also detected in unaffected family members (Evans et al. 2016. PubMed ID: 27322474; Bianchessi et al. 2020. PubMed ID: 32575496). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD and has conflicting interpretations of likely pathogenic and uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/404515/). Although we suspect this variant could be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Juvenile myelomonocytic leukemia Uncertain:1

Sep 29, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Sep 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1590W variant (also known as c.4768C>T), located in coding exon 35 of the NF1 gene, results from a C to T substitution at nucleotide position 4768. The arginine at codon 1590 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was reported in multiple individuals with features consistent with neurofibromatosis type 1 (Upadhyaya M et al. Hum Mutat, 1997;10:248-50; Barrea C et al. Neuropediatrics, 2018 Jun;49:180-184; Napolitano F et al. Genes (Basel), 2022 Jun;13:). 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 available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;.;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	-0.083	T
MutationAssessor	Uncertain	2.7	M;.;.
PhyloP100		3.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.6	D;D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.96
MutPred		0.65		Gain of ubiquitination at K1614 (P = 0.0641);.;.;
MVP		0.90
MPC		1.8
ClinPred		1.0	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.94
gMVP		0.92
Mutation Taster		=1/99	disease causing

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

Other links and lift over

dbSNP: rs1060500316; hg19: chr17-29592353; COSMIC: COSV62192826; COSMIC: COSV62192826;