17-31334930-CAA-C
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001042492.3(NF1):c.5907_5908delAA(p.Arg1970SerfsTer6) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000659 in 151,748 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 29)
Consequence
NF1
NM_001042492.3 frameshift
NM_001042492.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.87
Publications
6 publications found
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]
NF1 Gene-Disease associations (from GenCC):
- neurofibromatosis type 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
- neurofibromatosis-Noonan syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
- Moyamoya diseaseInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary pheochromocytoma-paragangliomaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial ovarian cancerInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-31334930-CAA-C is Pathogenic according to our data. Variant chr17-31334930-CAA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 216865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_001042492.3. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| NF1 | NM_001042492.3 | MANE Select | c.5907_5908delAA | p.Arg1970SerfsTer6 | frameshift | Exon 40 of 58 | NP_001035957.1 | ||
| NF1 | NM_000267.4 | c.5844_5845delAA | p.Arg1949SerfsTer6 | frameshift | Exon 39 of 57 | NP_000258.1 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| NF1 | ENST00000358273.9 | TSL:1 MANE Select | c.5907_5908delAA | p.Arg1970SerfsTer6 | frameshift | Exon 40 of 58 | ENSP00000351015.4 | ||
| NF1 | ENST00000356175.7 | TSL:1 | c.5844_5845delAA | p.Arg1949SerfsTer6 | frameshift | Exon 39 of 57 | ENSP00000348498.3 | ||
| NF1 | ENST00000579081.6 | TSL:1 | n.*1072_*1073delAA | non_coding_transcript_exon | Exon 40 of 58 | ENSP00000462408.2 |
Frequencies
GnomAD3 genomes 0.00000659 AC: 1AN: 151748Hom.: 0 Cov.: 29 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
151748
Hom.:
Cov.:
29
Gnomad AFR
AF:
Gnomad AMI
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Gnomad AMR
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Gnomad ASJ
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Gnomad EAS
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Gnomad NFE
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Gnomad OTH
AF:
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome 0.00000659 AC: 1AN: 151748Hom.: 0 Cov.: 29 AF XY: 0.0000135 AC XY: 1AN XY: 74076 show subpopulations
GnomAD4 genome
AF:
AC:
1
AN:
151748
Hom.:
Cov.:
29
AF XY:
AC XY:
1
AN XY:
74076
show subpopulations
African (AFR)
AF:
AC:
0
AN:
41286
American (AMR)
AF:
AC:
0
AN:
15218
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3464
East Asian (EAS)
AF:
AC:
0
AN:
5170
South Asian (SAS)
AF:
AC:
0
AN:
4804
European-Finnish (FIN)
AF:
AC:
0
AN:
10512
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
1
AN:
67988
Other (OTH)
AF:
AC:
0
AN:
2078
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
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0.95
Allele balance
Age Distribution
Genome Het
Variant carriers
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Age
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ClinVar
ClinVar submissions as Germline
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
7
-
-
Neurofibromatosis, type 1 (7)
1
-
-
Hereditary cancer-predisposing syndrome (1)
1
-
-
not provided (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
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Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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