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
Consequence
NM_001042492.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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NF1 | NM_001042492.3 | c.574C>T | p.Arg192* | stop_gained | Exon 5 of 58 | ENST00000358273.9 | NP_001035957.1 | |
NF1 | NM_000267.3 | c.574C>T | p.Arg192* | stop_gained | Exon 5 of 57 | NP_000258.1 | ||
NF1 | NM_001128147.3 | c.574C>T | p.Arg192* | stop_gained | Exon 5 of 15 | NP_001121619.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152018Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250636Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135602
GnomAD4 exome AF: 0.00000207 AC: 3AN: 1450592Hom.: 0 Cov.: 27 AF XY: 0.00000277 AC XY: 2AN XY: 722358
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152018Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74260
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:15
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PM2_Supporting+PVS1+PS4+PM6+PP1 -
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. -
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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. -
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PVS1, PS4, PP1, PM2_Supporting, PM6 -
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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 -
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not provided Pathogenic:7
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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. -
PP1, PP4, PM2, PM6, PS3, PVS1 -
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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. -
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
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See cases Pathogenic:1
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
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Juvenile myelomonocytic leukemia Pathogenic:1
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Neurofibroma;C0349639:Juvenile myelomonocytic leukemia Pathogenic:1
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Café-au-lait macules with pulmonary stenosis Pathogenic:1
PVS1,PS4,PM2,PM6 -
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at