17-31258406-A-T

Position:

• chr17-31258406-A-T

Variant summary

Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001042492.3(NF1):​c.4236A>T​(p.Arg1412Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1412T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 0.808

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 23 ACMG points.

• PS1: Transcript NM_001042492.3 (NF1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 639692
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 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 chr17-31258404-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 457686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 17-31258406-A-T is Pathogenic according to our data. Variant chr17-31258406-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 348.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31258406-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.4236A>T	p.Arg1412Ser	missense_variant	32/58	ENST00000358273.9
NF1	NM_000267.3	c.4173A>T	p.Arg1391Ser	missense_variant	31/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.4236A>T	p.Arg1412Ser	missense_variant	32/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Mar 29, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 25, 2023	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 1391 of the NF1 protein (p.Arg1391Ser). This missense change has been observed in individual(s) with neurofibromatosis type 1 (NF1) (PMID: 27322474). ClinVar contains an entry for this variant (Variation ID: 348). 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. Experimental studies have shown that this missense change affects NF1 function (PMID: 7581973, 9003501, 16513807, 22807134). This variant disrupts the p.Arg1391 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27322474; Invitae). 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. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 23, 2020

The NF1 c.4236A>T; p.Arg1412Ser variant (rs137854554), also known as c.4173A>T; p.Arg1391Ser for NM_000267, is reported in the literature in multiple individuals affected with neurofibromatosis (Evans 2016, Thomas 2012, Upadhyaya 1997). Functional analyses of the variant protein show a significant reduction in GTPase-activating activity and a reduced affinity for Ras (Thomas 2012, Upadhyaya 1997). This variant is also reported in ClinVar (Variation ID: 348). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Additionally, other variants at this codon (c.4236A>C, p.Arg1412Ser; c.4237A>G, p.Arg1412Gly; c.4238G>C, p.Arg1412Thr) have been reported in individuals with neurofibromatosis and are considered pathogenic (Evans 2016, Fokkema 2011, Thomas 2012). The arginine at codon 1412 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.808). Based on available information, this variant is considered to be likely pathogenic. References: Evans DG et al. Comprehensive RNA Analysis of the NF1 Gene in Classically Affected NF1 Affected Individuals Meeting NIH Criteria has High Sensitivity and Mutation Negative Testing is Reassuring in Isolated Cases With Pigmentary Features Only. EBioMedicine. 2016 May;7:212-20. Fokkema IF et al. LOVD v.2.0: the next generation in gene variant databases. Hum Mutat. 2011 May;32(5):557-63. Thomas L et al. Assessment of the potential pathogenicity of missense mutations identified in the GTPase-activating protein (GAP)-related domain of the neurofibromatosis type-1 (NF1) gene. Hum Mutat. 2012 Dec;33(12):1687-96. Upadhyaya M et al. Mutational and functional analysis of the neurofibromatosis type 1 (NF1) gene. Hum Genet. 1997 Jan;99(1):88-92. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 21, 2021

The p.R1391S variant (also known as c.4173A>T), located in coding exon 31 of the NF1 gene, results from an A to T substitution at nucleotide position 4173. The arginine at codon 1391 is replaced by serine, an amino acid with dissimilar properties. 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 alteration has been reported in at least two individuals with neurofibromatosis and has been shown to have reduction of GAP assisted GTP hydrolysis by Ras (Upadhyaya M et al. Hum. Genet., 1997 Jan;99:88-92). (Evans DG et al. EBioMedicine, 2016 May;7:212-20). Two additional disease-causing mutations, p.R1391G and p.R1391T, have been described in the same codon. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.;D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.8	H;.;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.8	D;D;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.98
MutPred		0.95		Loss of MoRF binding (P = 0.079);.;.;
MVP		0.99
MPC		1.3
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.99
gMVP		0.96

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: rs137854554; hg19: chr17-29585424;