rs748990989
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_Moderate
The NM_001042492.3(NF1):āc.4379A>Gā(p.His1460Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,452,932 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 Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1460D) has been classified as Uncertain significance.
Frequency
Consequence
NM_001042492.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.4379A>G | p.His1460Arg | missense_variant | 33/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.4316A>G | p.His1439Arg | missense_variant | 32/57 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.4379A>G | p.His1460Arg | missense_variant | 33/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000417 AC: 1AN: 239952Hom.: 0 AF XY: 0.00000772 AC XY: 1AN XY: 129556
GnomAD4 exome AF: 0.00000275 AC: 4AN: 1452932Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 2AN XY: 722248
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 10, 2021 | This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 1439 of the NF1 protein (p.His1439Arg). This variant is present in population databases (rs748990989, gnomAD 0.001%). This missense change has been observed in individual(s) with neurofibromatosis type 1 (PMID: 23668869). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 641811). - |
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 30, 2023 | The p.H1439R variant (also known as c.4316A>G), located in coding exon 32 of the NF1 gene, results from an A to G substitution at nucleotide position 4316. The histidine at codon 1439 is replaced by arginine, an amino acid with highly similar properties. This alteration has been observed in one patient from a cohort of 78 Korean patients with NF1-related disease (Ko JM et al. Pediatr Neurol, 2013 Jun;48:447-53). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis.Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at