rs754023358
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001042492.3(NF1):c.4635C>A(p.Tyr1545Ter) variant causes a stop gained change involving the alteration of a non-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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y1545Y) has been classified as Likely benign. 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 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.4635C>A | p.Tyr1545Ter | stop_gained | 35/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.4572C>A | p.Tyr1524Ter | stop_gained | 34/57 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.4635C>A | p.Tyr1545Ter | stop_gained | 35/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 11, 2014 | The p.Y1545* pathogenic mutation (also known as c.4635C>A) located in coding exon 35 of the NF1 gene, results from a C to A substitution at nucleotide position 4635. This changes the amino acid from a tyrosine to a stop codon within coding exon 35.<span style="background-color: initial;">This pathogenic alteration was described in two individuals with neurofibromatosis type 1 out of a cohort of 565 affected individuals. (<span style="background-color: initial;">Sabbagh A, et al.Hum. Mutat. 2013 Nov; 34(11):1510-8).<span style="background-color: initial;">Additionally, this pathogenic alteration was described in one individual with neurofibromatosis type 1 out of a cohort of 113 affected individuals. (<span style="background-color: initial;">Garcia-Linares C, et al.Hum. Mutat. 2011 Jan; 32(1):78-90). In addition to the clinical data presented in the literature, s<span style="background-color: initial;">ince premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at