NM_001042492.3:c.574C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001042492.3(NF1):​c.574C>T​(p.Arg192*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000312 in 1,602,610 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: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

NF1
NM_001042492.3 stop_gained

Scores

2
4
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:29

Conservation

PhyloP100: 2.66
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 17-31169985-C-T is Pathogenic according to our data. Variant chr17-31169985-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 40093.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31169985-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NF1NM_001042492.3 linkc.574C>T p.Arg192* stop_gained Exon 5 of 58 ENST00000358273.9 NP_001035957.1 P21359-1
NF1NM_000267.3 linkc.574C>T p.Arg192* stop_gained Exon 5 of 57 NP_000258.1 P21359-2
NF1NM_001128147.3 linkc.574C>T p.Arg192* stop_gained Exon 5 of 15 NP_001121619.1 P21359-5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NF1ENST00000358273.9 linkc.574C>T p.Arg192* stop_gained Exon 5 of 58 1 NM_001042492.3 ENSP00000351015.4 P21359-1

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152018
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250636
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135602
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000882
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000207
AC:
3
AN:
1450592
Hom.:
0
Cov.:
27
AF XY:
0.00000277
AC XY:
2
AN XY:
722358
show subpopulations
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:
0.00000272
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152018
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74260
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:29
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:15
-
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 01, 2007
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

-
Juno Genomics, Hangzhou Juno Genomics, Inc
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PM2_Supporting+PVS1+PS4+PM6+PP1 -

Jan 22, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg192*) 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 (rs397514641, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10712197, 10726756, 15146469, 16835897, 21278392, 26056819, 27838393). ClinVar contains an entry for this variant (Variation ID: 40093). For these reasons, this variant has been classified as Pathogenic. -

Mar 15, 2022
Genome-Nilou Lab
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 01, 2023
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 01, 2016
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 20, 2023
Neuberg Centre For Genomic Medicine, NCGM
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The stop gained c.574C>T (p.Arg192Ter) variant in the NF1 gene has been reported previously in has been observed in individual(s) with neurofibromatosis type 1 (Toliat, M R et al.,2000). This variant is reported with the allele frequency (0.0003%) in the gnomAD Exome. It is submitted to ClinVar as Pathogenic (multiple submissions). Computational evidence (MutationTaster - Disease causing) predicts damaging effect on protein structure and function for this variant. This variant is predicted to cause loss of normal protein function through protein truncation. The nucleotide change c.574C>T in NF1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -

Oct 26, 2020
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 06, 2022
MGZ Medical Genetics Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 09, 2021
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PVS1, PS4, PP1, PM2_Supporting, PM6 -

May 15, 2022
Institute of Medical Genetics, University of Zurich
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 02, 2022
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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 with neurofibromatosis type 1 (MIM#162200). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (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) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with neurofibromatosis type 1 (PMID: 27838393). (SP) 1205 - This variant has been shown to be maternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Dec 20, 2019
Medical Genetics, University of Parma
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 11, 2024
NHS Central & South Genomic Laboratory Hub
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:7
Feb 01, 2021
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Apr 19, 2021
Athena Diagnostics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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 unrelated individuals with clinical features associated with this gene. -

Jul 23, 2024
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PP1, PP4, PM2, PM6, PS3, PVS1 -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Apr 19, 2021
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The NF1 c.574C>T (p.Arg192*) variant causes the premature termination of NF1 protein synthesis. This variant has been reported in the published literature in multiple individuals and families with NF1 in the published literature (PMID: 27838393 (2017), 26056819 (2015), 21278392 (2011), 19142971 (2009), 17406642 (2007), 16835897 (2006), 15146469 (2004), 10862084 (2000), 10726756 (2000), 10712197 (2000)). The frequency of this variant in the general population, 0.000004 (1/250636 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Mar 28, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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; This variant is associated with the following publications: (PMID: 10726756, 15846561, 19142971, 17353900, 17406642, 10712197, 10862084, 12095621, 15146469, 27625798, 25525159, 26056819, 27838393, 28529006, 31347283, 31717729, 30613976, 32581362, 31370276, 31776437) -

Axillary freckling;C1861975:Cafe au lait spots, multiple;C4024926:Focal T2 hyperintense basal ganglia lesion Pathogenic:1
Jan 01, 2017
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

See cases Pathogenic:1
Mar 01, 2023
Institute of Human Genetics, University Hospital Muenster
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG categories: PVS1,PM1,PP5 -

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
Mar 09, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Juvenile myelomonocytic leukemia Pathogenic:1
Dec 07, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Neurofibroma;C0349639:Juvenile myelomonocytic leukemia Pathogenic:1
-
NIHR Bioresource Rare Diseases, University of Cambridge
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Café-au-lait macules with pulmonary stenosis Pathogenic:1
Oct 04, 2024
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

PVS1,PS4,PM2,PM6 -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1
Apr 18, 2022
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.R192* pathogenic mutation (also known as c.574C>T), located in coding exon 5 of the NF1 gene, results from a C to T substitution at nucleotide position 574. This changes the amino acid from an arginine to a stop codon within coding exon 5. This mutation has been identified in numerous individuals who meet clinical criteria for neurofibromatosis type 1 (NF1) (Toliat MR et al. Electrophoresis. 2000 Feb;21:541-4; Fahsold R et al. Am. J. Hum. Genet. 2000 Mar;66:790-818; De Luca A et al. Hum. Mutat. 2004 Jun;23:629; Lee MJ et al. Hum. Mutat. 2006 Aug;27:832; Cali F et. al Eur J Med Genet. 2017 Feb;60(2):93-99; Wu-Chou YH et al. J. Biomed. Sci. 2018 Oct;25(1):72). 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
0.57
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
36
DANN
Uncertain
1.0
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Uncertain
0.86
D
Vest4
0.98, 0.98, 0.99
GERP RS
3.6

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397514641; hg19: chr17-29497003; COSMIC: COSV62197492; COSMIC: COSV62197492; API