rs1057520334

chr17-31095355-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM5 PP2

The NM_001042492.3(NF1):c.46C>T(p.Arg16Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R16P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.79

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]

MIR4733HG (HGNC:55332): (MIR4733 host gene)

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in NM_001042492.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-31095356-G-C is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, NF1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.46C>T	p.Arg16Cys	missense_variant	1/58	ENST00000358273.9
NF1	NM_000267.3	c.46C>T	p.Arg16Cys	missense_variant	1/57
NF1	NM_001128147.3	c.46C>T	p.Arg16Cys	missense_variant	1/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.46C>T	p.Arg16Cys	missense_variant	1/58	1	NM_001042492.3	P1
MIR4733HG	ENST00000583377.1	n.96G>A		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1387796 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 684830

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 27, 2022	Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 378270). This variant has not been reported in the literature in individuals affected with NF1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 16 of the NF1 protein (p.Arg16Cys). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 27, 2016

The R16C variant in the NF1 gene has not, to our knowledge, been published in the literature as pathogenic or benign. This variant was not observed in approximately 5,600 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The R16C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analyses predict that this variant is probably damaging to the protein structure and function. A missense variant in the same residue (R16P) has been reported in an individual with clinical featues and a family history associated with neurofibromatosis (Nemethova et al., 2013), supporting the functional importance of this region of the protein. We interpret R16C as a variant of uncertain significance -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 06, 2019

The p.R16C variant (also known as c.46C>T), located in coding exon 1 of the NF1 gene, results from a C to T substitution at nucleotide position 46. The arginine at codon 16 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Pathogenic	31
Dann	Uncertain	1.0
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.50	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Uncertain	0.65	D;D;D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.5	M;M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.92	D
Polyphen		1.0	D;D;D;.
Vest4		0.63, 0.64, 0.51
MutPred		0.57		Loss of MoRF binding (P = 0.0301);Loss of MoRF binding (P = 0.0301);Loss of MoRF binding (P = 0.0301);Loss of MoRF binding (P = 0.0301);
MVP		0.72
MPC		1.0
ClinPred		1.0	D
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.58
gMVP		0.86

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: rs1057520334; hg19: chr17-29422373;