rs587781821

Positions:

• chr17-31225104-A-G
• chr17-31225104-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001042492.3(NF1):​c.1855A>G​(p.Arg619Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 2.95

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.24307317).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.1855A>G	p.Arg619Gly	missense_variant	17/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.1855A>G	p.Arg619Gly	missense_variant	17/57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.1855A>G	p.Arg619Gly	missense_variant	17/58	1	NM_001042492.3	ENSP00000351015	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251102 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135752

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461394 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727000

Gnomad4 AFR exome AF: 0.0000299

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.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

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	Labcorp Genetics (formerly Invitae), Labcorp	Nov 01, 2023	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 619 of the NF1 protein (p.Arg619Gly). This variant is present in population databases (rs587781821, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 141531). 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 not expected to disrupt NF1 protein function with a negative predictive value of 95%. 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. -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Mar 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 24, 2014	The p.R619G variant (also known as c.1855A>G), located in coding exon 17 of the NF1 gene, results from an A to G substitution at nucleotide position 1855. The arginine at codon 619 is replaced by glycine, an amino acid with dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species.In addition, this alteration is predicted to be possibly damaging and tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.R619G remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 15, 2017

This variant is denoted NF1 c.1855A>G at the cDNA level, p.Arg619Gly (R619G) at the protein level, and results in the change of an Arginine to a Glycine (AGA>GGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NF1 Arg619Gly was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. NF1 Arg619Gly occurs at a position that is conserved across species and is located within the GTPase activating protein domain (Luo 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether NF1 Arg619Gly is a pathogenic or benign variant. We consider it to be 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 17, 2022

The c.1855A>G (p.R619G) alteration is located in exon 17 (coding exon 17) of the NF1 gene. This alteration results from a A to G substitution at nucleotide position 1855, causing the arginine (R) at amino acid position 619 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;.;T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;.
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.0080	D;D;D
Sift4G	Benign	0.47	T;T;T
Polyphen		0.72	P;P;.
Vest4		0.89
MutPred		0.35		Loss of MoRF binding (P = 0.0427);Loss of MoRF binding (P = 0.0427);.;
MVP		0.89
MPC		0.89
ClinPred		0.38	T
GERP RS		5.3
Varity_R		0.11
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs587781821; hg19: chr17-29552122;