17-31235623-C-T

Position:

• chr17-31235623-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.3721C>T​(p.Arg1241Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,766 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R1241R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NF1 NM_001042492.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:18
• Conservation: PhyloP100: 2.78

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 17-31235623-C-T is Pathogenic according to our data. Variant chr17-31235623-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31235623-C-T is described in Lovd as [Pathogenic]. Variant chr17-31235623-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.3721C>T	p.Arg1241Ter	stop_gained	28/58	ENST00000358273.9
NF1	NM_000267.3	c.3721C>T	p.Arg1241Ter	stop_gained	28/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.3721C>T	p.Arg1241Ter	stop_gained	28/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461766 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727186

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:10

Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Jan 21, 2015	- -
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	Baylor Genetics	Nov 14, 2019	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing by following sources [PMID: 10712197, 28152038, 25525159, 25624686, 17889038, 29620724, 29089047, 12483293, ClinVar ID: 361] -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	This sequence change creates a premature translational stop signal (p.Arg1241*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10712197, 12483293, 16835897, 23668869, 25624686). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 361). For these reasons, this variant has been classified as Pathogenic. -
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	Genome-Nilou Lab	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Medical Genetics, University of Parma	Dec 20, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	May 08, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 16, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated juvenile myelomonocytic leukemia (MIM#607785), familial spinal neurofibromatosis (MIM#162210), neurofibromatosis type 1 (MIM#162200), neurofibromatosis-Noonan syndrome (MIM#601321) and Watson syndrome (MIM#193520). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Disease manifestation can be extremely variable, even within a family (GeneReviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other null variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Other NMD-predicted variants have been classified as likely pathogenic or pathogenic (DECIPHER). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical diagnostic laboratories and has been reported in multiple unrelated individuals with neurofibromatosis type 1 (ClinVar; PMIDs: 16835897, 33919865). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 28, 2022	PP4, PM2, PM6, PS4_moderate, PVS1 -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 20, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 08, 2018	The NF1 c.3721C>T; p.Arg1241Ter variant (rs137854562) is reported in the literature in several individuals with NF1 (Fahsold 2000, Gupta 2015, Ko 2013, Lee 2006, Upadhyaya 2003). This variant is reported as pathogenic in ClinVar (Variation ID: 361). It is absent from the 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. Based on available information, this variant is considered to be 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. Gupta V et al. Rare case of optic pathway glioma with extensive intra-ocular involvement in a child with neurofibromatosis type 1. Middle East Afr J Ophthalmol. 2015 Jan-Mar;22(1):117-8. Ko JM et al. Mutation spectrum of NF1 and clinical characteristics in 78 Korean patients with neurofibromatosis type 1. Pediatr Neurol. 2013 Jun;48(6):447-53. Lee MJ et al. Identification of forty-five novel and twenty-three known NF1 mutations in Chinese patients with neurofibromatosis type 1. Hum Mutat. 2006 Aug;27(8):832. Upadhyaya M et al. Three different pathological lesions in the NF1 gene originating de novo in a family with neurofibromatosis type 1. Hum Genet. 2003 Jan;112(1):12-7. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25049327, 28152038, 22962301, 29620724, 25525159, 12483293, 27236105, 24931142, 31730495, 31717729, 25624686, 10712197, 30530636, 17889038, 26230854, 15060124, 29089047, 16835897, 23668869) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2014

- -

Juvenile myelomonocytic leukemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0	A;A
Vest4		1.0
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs137854562; hg19: chr17-29562641; COSMIC: COSV62191467;