rs786202112

chr17-31327839-G-Achr17-31327839-G-Cchr17-31327839-G-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001042492.3(NF1):c.5609G>A(p.Arg1870Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/25 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as 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. R1870P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NF1 NM_001042492.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 9.56

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 19 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 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 chr17-31327839-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1070186.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, NF1
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 17-31327839-G-A is Pathogenic according to our data. Variant chr17-31327839-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 185354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31327839-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.5609G>A	p.Arg1870Gln	missense_variant, splice_region_variant	38/58	ENST00000358273.9
NF1	NM_000267.3	c.5546G>A	p.Arg1849Gln	missense_variant, splice_region_variant	37/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.5609G>A	p.Arg1870Gln	missense_variant, splice_region_variant	38/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461166 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726922

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1849 of the NF1 protein (p.Arg1849Gln). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with neurofibromatosis 1 (NF1) (PMID: 10607834, 10712197, 10862084, 10980545, 11857752, 12807981, 18484666, 18546366, 23668869, 23913538, 24932921, 25325900). ClinVar contains an entry for this variant (Variation ID: 185354). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 37, also known as exon 29 and introduces a premature termination codon (PMID: 10607834, 10980545; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Missense variant: previously reported to alter splicing and result in a loss of normal protein fucnction through nonsense-mediated decay (NMD) or protein truncation (PMID:. 10607834. Predicted Consequence/Location:). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000185354). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 10862084, 10980545, 12807981, 25325900, 29673180, 31776437). A different missense change at the same codon (p.Arg1870Leu) has been reported to be associated with NF1 related disorder (ClinVar ID: VCV001070186). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 26, 2020	- -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.5546G>A;p.(Arg1849Gln) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 185354; PMID: 23668869; 16937374; 10862084; 10980545; 11857752; 12807981; 10607834) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 16937374; 18546366; 10862084; 10980545) - PS3. This variant is not present in population databases (rs786202112, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Missense variant in NF1 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2023	Published functional studies demonstrate a damaging effect: aberrant splicing resulting in transcripts lacking exon 37 or exons 37 and 38, also called exons 29 and 30 using alternate exon numbering (Girodon-Boulandet et al., 2000; Messiaen et al., 2000); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing; This variant is associated with the following publications: (PMID: 16830335, 30014477, 10862084, 29673180, 25325900, 34418705, 23668869, 25403449, 10712197, 27322474, 19292874, 10607834, 24932921, 29489754, 28955729, 28152038, 10980545, 29618358, 31766501, 16937374, 31776437, 33372952, 33877690, 23913538) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 26, 2023	PM2, PS4_moderate, PVS1 -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2023

The c.5546G>A (p.R1849Q) alteration is located in coding exon 37 of the NF1 gene. This alteration results from a G to A substitution at nucleotide position 5546, causing the arginine (R) at amino acid position 1849 to be replaced by a glutamine (Q). This change occurs in the last base pair of coding exon37, which makes it likely to have some effect on normal mRNA splicing. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been detected in multiple individuals with a clinical diagnosis of neurofibromatosis type 1 (Ars, 2000; Rübben, 2006; Ko, 2013; Anastasaki, 2017; Palma Milla, 2018). This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. RNA studies have demonstrated that this variant results in skipping of coding exon 37 (Ars, 2000; Pros, 2006; Ambry internal data). In silico splice site analysis predicts that this alteration may weaken the native splice donor site. This amino acid alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Rhabdomyosarcoma Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Sep 01, 2020

- -

Neurofibromatosis, type 1;C0349639:Juvenile myelomonocytic leukemia;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Juvenile myelomonocytic leukemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 07, 2022

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2015

The p.R1870Q pathogenic mutation (also known as c.5609G>A) is located in coding exon 38 of the NF1 gene. This pathogenic mutation results from a G to A substitution at nucleotide position 5609. The amino acid change results in an arginine to glutamine at codon 1870, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 38, which makes it likely to have some effect on normal mRNA splicing. This mutation was first described in one familial and two sporadic cases of neurofibromatosis type 1 (NF1). These researchers performed further functional studies and demonstrated a skipping of exon 38, leading to a truncated protein (Ars E, Hum. Mol. Genet. 2000 Jan; 9(2):237-47). This mutation was also identified in two unrelated individuals of Korean descent with NF1 (Ko JM, Pediatr. Neurol. 2013 Jun; 48(6):447-53) as well as in one family of Indonesian descent with NF1 (Rübben A, Mol. Cancer 2006 ; 5():36). 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. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 55000 alleles tested) in our clinical cohort. Based on nucleotide sequence alignment, this position is completely conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native donor splice site, but is predicted to weaken (but not abolish) the efficacy of the native donor splice site by ESEfinder. In the published literature, this alteration is also referred to as c.5546G>A (R1849Q). Based on the available evidence, p.R1870Q is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Pathogenic	35
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;.;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Pathogenic	3.3	M;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.5	D;D;D;.
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;.
Polyphen		1.0	D;D;.;.
Vest4		0.98
MVP		0.96
MPC		2.4
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.32		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs786202112; hg19: chr17-29654857; COSMIC: COSV62210316; COSMIC: COSV62210316;