17-31229061-C-T

Position:

• chr17-31229061-C-T

Variant summary

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

The ENST00000358273.9(NF1):​c.2446C>T​(p.Arg816Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,218 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. R816R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NF1 ENST00000358273.9 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:20
• Conservation: PhyloP100: 3.55

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 17-31229061-C-T is Pathogenic according to our data. Variant chr17-31229061-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 280055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31229061-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.2446C>T	p.Arg816Ter	stop_gained	21/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.2446C>T	p.Arg816Ter	stop_gained	21/57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.2446C>T	p.Arg816Ter	stop_gained	21/58	1	NM_001042492.3	ENSP00000351015	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459218 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725870

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:10

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	Medical Genetics, University of Parma	Dec 20, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	NHS Central & South Genomic Laboratory Hub	Jul 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 01, 2023	This sequence change creates a premature translational stop signal (p.Arg816*) 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 NF1-related conditions (PMID: 9150739, 9475595, 10712197, 15146469, 18484666, 19142971, 23668869, 25403449). ClinVar contains an entry for this variant (Variation ID: 280055). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 02, 2023	Criteria applied: PVS1,PS3_MOD,PS4_MOD,PM2_SUP -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Feb 05, 2020	- -
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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 07, 2024	Variant summary: NF1 c.2446C>T (p.Arg816X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 250020 control chromosomes. c.2446C>T has been reported in the literature in multiple heterozygous individuals affected with Neurofibromatosis Type 1 (Maynard_1997, Bahuau_1998). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 9475595, 9150739). ClinVar contains an entry for this variant (Variation ID: 280055). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Apr 05, 2021	PVS1, PS4, PM2 -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2020	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; Observed in multiple patients with Neurofibromatosis type 1 referred for genetic testing at GeneDx and in published literature, including both apparent and confirmed de novo observations (Maynard 1997, Fahsold 2000, Jeong 2006, Ko 2013, Cali 2016, Pemov 2017, Cannon 2018, Tsipi 2018); Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 25525159, 10712197, 30192422, 15146469, 32486389, 32408052, 9150739, 23668869, 9475595, 27838393, 16479075, 27498913, 25403449, 30014477, 19142971, 26969325, 18484666, 16773574, 29146900, 31730495, 29415745, 28068329, 30308447, 31766501, 31776437) -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 31, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 20, 2023	PP1_strong, PM2_moderate, PS2, PS4_moderate, PVS1 -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Inguinal freckling;C1860334:Lisch nodules;C1860335:Axillary freckling;C1861975:Cafe au lait spots, multiple;C4023681:Delayed fine motor development;C4025174:Large cafe-au-lait macules with irregular margins Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

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 21, 2023

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2022

The p.R816* variant (also known as c.2446C>T), located in coding exon 21 of the NF1 gene, results from a C to T substitution at nucleotide position 2446. This changes the amino acid from an arginine to a stop codon within coding exon 21. This mutation has been reported multiple times in individuals with clinical features of neurofibromatosis type 1 (Maynard et al. Hum. Genet. 1997; 99:674-76; Bahuau et al. Am J Med Genet. 1998;75(3):265-72; Fahsold et al. Am. J. Hum. Genet. 2000; 66(3):790-818; Jeong et al. J. Korean Med. Sci. 2006;21(1):107-12; Bottillo et al. J. Pathol. 2009; 217(5):693-701; Stenman et al. Endocr. Pathol. 2015; 26(1):9-14; Kang E et al. J Hum Genet, 2020 Jan;65:79-89; N Abdel-Aziz N et al. Mol Genet Genomic Med, 2021 12;9:e1631). This mutation also segregated with disease in ten individuals from one family with neurofibromatosis (Bahuau et al. Am J Med Genet. 1998. 23;75(3):265-72). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	A;A
Vest4		0.98
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs886041347; hg19: chr17-29556079; COSMIC: COSV62196183; COSMIC: COSV62196183;