17-31249093-C-T

Position:

• chr17-31249093-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001042492.3(NF1):​c.4084C>T​(p.Arg1362Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000342 in 1,461,810 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: NF1 NM_001042492.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:19
• Conservation: PhyloP100: 3.68

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-31249093-C-T is Pathogenic according to our data. Variant chr17-31249093-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31249093-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.4084C>T	p.Arg1362Ter	stop_gained	30/58	ENST00000358273.9
NF1	NM_000267.3	c.4084C>T	p.Arg1362Ter	stop_gained	30/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.4084C>T	p.Arg1362Ter	stop_gained	30/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251344 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135840

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

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: 0.00000342 AC: 5 AN: 1461810 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727212

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:11

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 05, 2024	This sequence change creates a premature translational stop signal (p.Arg1362*) in the NF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). This variant is present in population databases (rs137854560, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 (PMID: 9003501, 10543400, 10712197, 12112660, 24789688; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 344). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Medical Genetics, University of Parma	Dec 20, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Apr 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 26, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Aug 29, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	Feb 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Sep 27, 2023	PVS1, PS4, PM2, PP5 - The variant has been reported in ClinVar by other laboratories (Variation ID 344). Loss-of-function variants in NF1 are known to be pathogenic (PMID: 23913538). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2000	- -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 05, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 06, 2022	PP4, PM2, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 14, 2022	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple individuals with clinical features associated with this gene. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Identified in patients with clinically diagnosed neurofibromatosis type 1 in published literature (Fahsold 2000, Evans 2016, Tsipi 2018); This variant is associated with the following publications: (PMID: 28852190, 28356599, 27236105, 10712197, 9003501, 25525159, 25541118, 27322474, 23668869, 14517963, 23913538, 24789688, 12112660, 10543400, 30308447, 29625052, 31776437, 31717729, 33674644) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 29, 2018	The NF1 c.4084C>T; p.Arg1362Ter variant (rs137854560) is reported in the medical literature in individuals with neurofibromatosis type I (Fahsold 2000, Messiaen 2000, Upadhyaya 1997). The variant is listed in the ClinVar database (Variation ID: 344) as pathogenic by several sources. This variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Considering available information, this variant is classified as pathogenic. References: Fahsold R et al. Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. Am J Hum Genet. 2000 Mar;66(3):790-818. Messiaen LM et al. Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects. Hum Mutat. 2000;15(6):541-55. Upadhyaya M et al. Mutational and functional analysis of the neurofibromatosis type 1 (NF1) gene. Hum Genet. 1997 Jan;99(1):88-92. -

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

Jan 19, 2022

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 30, 2015

The p.R1362* pathogenic mutation (also known as c.4084C>T), located in coding exon 30 of the NF1 gene, results from a C to T substitution at nucleotide position 4084. This changes the amino acid from an arginine to a stop codon within coding exon 30. This mutation has beendetectedin multipleindividuals satisfying NIH diagnostic criteria for NF1 (FahsoldRet al.Am. J. Hum. Genet. 2000; 66(3):790-818;Ko JMet al.Pediatr.Neurol. 2013; 48(6):447-53;KluweLet al.Hum.Mutat. 2003; 22(5):420).In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008; 10:294). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Benign	0.69	D
MutationTaster	Benign	1.0	A;A
Vest4		0.99
GERP RS		4.8

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: rs137854560; hg19: chr17-29576111; COSMIC: COSV62191433;