17-31233115-C-G

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001042492.3(NF1):c.3610C>G(p.Arg1204Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,868 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1204Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 7.54

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 17 ACMG points.

• PM1: In a hotspot region, there are 4 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 chr17-31233116-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 384082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, NF1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914
• PP5: Variant 17-31233115-C-G is Pathogenic according to our data. Variant chr17-31233115-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31233115-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.3610C>G	p.Arg1204Gly	missense_variant	27/58	ENST00000358273.9
NF1	NM_000267.3	c.3610C>G	p.Arg1204Gly	missense_variant	27/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.3610C>G	p.Arg1204Gly	missense_variant	27/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251386 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135844

Gnomad AFR exome AF: 0.00

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: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461868 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727232

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: 0.0000187

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 06, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects NF1 function (PMID: 22807134). 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: 68337). This missense change has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10336779, 26635368, 27322474; Invitae). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs199474732, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 1204 of the NF1 protein (p.Arg1204Gly). -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Apr 25, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 07, 2023	The de novo c.3610C>G p.(Arg1204Gly) missense variant identified in NF1 has been reported in the literature in multiple individuals with Neurofibromatosis Type 1 [PMID: 10336779, 22807134; 31370276]. The c.3610C>G variant has been deposited in ClinVar as Likely Pathogenic/Pathogenic bymultiple submitters [ClinVar ID: 68337], is absent from the gnomAD v3.1.2 and TOPMed Freeze 8 databases and has an allele frequency of 0.000003978 in the gnomAD v2.1.1 database, suggesting it is not a common benign variant in the populations represented in those databases. The c.3610C>G variant is located in exon27 of this 58-exon gene and is predicted to replace a highly conserved arginine with glycine at position 1204 of the encoded protein. In silico predictions neither support or refute a damaging effect [REVEL 0.571], but functional studies conducted in vitro have shown association with significantly elevated levels of activatedGTP-bound Ras by comparison with the wild-type NF1 protein [PMID: 22807134]. Three other variants at the same codon, p.(Arg1204Trp), p.(Arg1204Leu) andp.(Arg1204Gln), have also been reported [PMID: 22807134, 26635368]. Based on the available evidence, the de novo c.3610C>G p.(Arg1204Gly)missense variant identified in the NF1 gene is reported as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 26, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Oct 07, 2022	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 supporting, PM5 moderated, PM6 moderated, PP2 supporting -

not provided Pathogenic:4 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 13, 2023	Published functional studies support a damaging effect: significant reduction in GTPase activity and mild reduction of interaction with SPRED1 (Thomas et al., 2012; Hirata et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27322474, 22807134, 26633542, 26635368, 24803665, 10712197, 10336779, 23447461, 31370276, 31766501, 25486365) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 22, 2020	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least two individuals with clinical features associated with this gene, with one of those appearing to occur de novo. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies show a reduction in activity of the GAP-related domain of NF1 (PMID: 22807134, 26635368). Computational tools predict that this variant is damaging. -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2019

The p.R1204G variant (also known as c.3610C>G), located in coding exon 27 of the NF1 gene, results from a C to G substitution at nucleotide position 3610. The arginine at codon 1204 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been identified an individual meeting NF1 diagnostic criteria (Krkljus S et al. Hum. Mutat., 1998;11:411). This variant has also been detected de novo in multiple unrelated individuals with NF1 (Hirata Y et al. J. Biol. Chem., 2016 Feb;291:3124-34). Experimental studies indicate that this variant will disrupt protein function (Thomas L et al. Hum. Mutat., 2012 Dec;33:1687-96). A different alteration at the same amino acid position, p.R1204W, has been identified in an individual meeting NF1 diagnostic criteria (Ars E et al. Hum. Mol. Genet., 2000 Jan;9:237-47). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this variant is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.;T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.6	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.8	D;D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.29	B;D;.
Vest4		0.97
MutPred		0.72		Loss of stability (P = 0.0813);Loss of stability (P = 0.0813);.;
MVP		0.94
MPC		1.9
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.75
gMVP		0.90

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: rs199474732; hg19: chr17-29560133;