rs786203038
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP2
The NM_001042492.3(NF1):c.122A>C(p.Glu41Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,524 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E41V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001042492.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.122A>C | p.Glu41Ala | missense_variant | 2/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.122A>C | p.Glu41Ala | missense_variant | 2/57 | ||
NF1 | NM_001128147.3 | c.122A>C | p.Glu41Ala | missense_variant | 2/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.122A>C | p.Glu41Ala | missense_variant | 2/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251180Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135756
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461524Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727074
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 13, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 41 of the NF1 protein (p.Glu41Ala). This variant is present in population databases (rs786203038, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 186556). 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. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 12, 2015 | The p.E41A variant (also known as c.122A>C), located in coding exon 2 of the NF1 gene, results from an A to C substitution at nucleotide position 122. The glutamic acid at codon 41 is replaced by alanine, an amino acid with dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6502 samples (13004 alleles) with coverage at this position.<span style="background-color:initial">To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 55000 alleles tested) in our clinical cohort.<span style="background-color:initial">This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.<span style="background-color:initial">Since supporting evidence is limited at this time, the clinical significance of p.E41A remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at