rs1555535189
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1PP2BS2_Supporting
The NM_001042492.3(NF1):āc.7030A>Gā(p.Thr2344Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T2344I) has been classified as Uncertain significance.
Frequency
Consequence
NM_001042492.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.7030A>G | p.Thr2344Ala | missense_variant | 47/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.6967A>G | p.Thr2323Ala | missense_variant | 46/57 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.7030A>G | p.Thr2344Ala | missense_variant | 47/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461864Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727230
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 06, 2023 | This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 2323 of the NF1 protein (p.Thr2323Ala). This variant is not present in population databases (gnomAD no frequency). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NF1 protein function. ClinVar contains an entry for this variant (Variation ID: 481960). This variant has not been reported in the literature in individuals affected with NF1-related conditions. - |
NF1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 30, 2022 | The NF1 c.7030A>G variant is predicted to result in the amino acid substitution p.Thr2344Ala. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/481960/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 10, 2021 | The p.T2323A variant (also known as c.6967A>G), located in coding exon 46 of the NF1 gene, results from an A to G substitution at nucleotide position 6967. The threonine at codon 2323 is replaced by alanine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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