rs1555618846
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM4PP3PP5_Moderate
The NM_001042492.3(NF1):c.4529_4543del(p.Leu1510_Asn1514del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
NF1
NM_001042492.3 inframe_deletion
NM_001042492.3 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.25
Genes affected
NF1 (HGNC:7765): (neurofibromin 1) This gene product appears to function as a negative regulator of the ras signal transduction pathway. Mutations in this gene have been linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. The mRNA for this gene is subject to RNA editing (CGA>UGA->Arg1306Term) resulting in premature translation termination. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_001042492.3
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_001042492.3.
PP3
?
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
?
Variant 17-31260464-GTCTACTCTGGAACAA-G is Pathogenic according to our data. Variant chr17-31260464-GTCTACTCTGGAACAA-G is described in ClinVar as [Pathogenic]. Clinvar id is 527466.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.4529_4543del | p.Leu1510_Asn1514del | inframe_deletion | 34/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.4466_4480del | p.Leu1489_Asn1493del | inframe_deletion | 33/57 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.4529_4543del | p.Leu1510_Asn1514del | inframe_deletion | 34/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 14, 2023 | This variant, c.4466_4480del, results in the deletion of 5 amino acid(s) of the NF1 protein (p.Leu1489_Asn1493del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). 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: 527466). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts a region of the NF1 protein in which other variant(s) (p.Leu1490Pro) have been determined to be pathogenic (PMID: 25541118, 26635368, 29914388). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at