17-31232832-G-A
Variant summary
Our verdict is Pathogenic. Variant got 25 ACMG points: 25P and 0B. PS1_Very_StrongPM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_001042492.3(NF1):c.3447G>A(p.Met1149Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1149R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001042492.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 25 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.3447G>A | p.Met1149Ile | missense_variant | 26/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.3447G>A | p.Met1149Ile | missense_variant | 26/57 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.3447G>A | p.Met1149Ile | missense_variant | 26/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 23, 2019 | For these reasons, this variant has been classified as Pathogenic. A different variant (c.3447G>T) giving rise to the same protein effect observed here (p.Met1149Ile) has been determined to be pathogenic (Invitae), indicating that this residue may be critical for protein function.. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been reported in several individuals affected with neurofibromatosis type 1, being found to be de novo in one case (PMID: 16944272, 27322474). ClinVar contains an entry for this variant (Variation ID: 420079). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with isoleucine at codon 1149 of the NF1 protein (p.Met1149Ile). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and isoleucine. - |
Pathogenic, criteria provided, single submitter | clinical testing | UAB Medical Genomics Laboratory, UAB Medicine | Jun 05, 2019 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 24, 2018 | This variant is denoted NF1 c.3447G>A at the cDNA level, p.Met1149Ile (M1149I) at the protein level, and results in the change of a Methionine to an Isoleucine (ATG>ATA). This variant was observed as a de novo finding in one individual with a clinical diagnosis of Neurofibromatosis Type 1 and was not identified in greater than 200 normal chromosomes evaluated (Griffiths 2007). NF1 Met1149Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Methionine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. NF1 Met1149Ile occurs at a position that is conserved across species and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on the currently available evidence, we consider NF1 Met1149Ile to be a likely pathogenic variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at