rs1555535032
Variant summary
Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1PS3PM2PP5_Very_Strong
The NM_001042492.3(NF1):c.6852_6855delTTAC(p.Tyr2285ThrfsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,962 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV007097379: Classified as Pathogenic per ACMG/AMP criteria (PVS1, PM2, PS3_supporting).". Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
NF1
NM_001042492.3 frameshift
NM_001042492.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.62
Publications
2 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
- neurofibromatosis-Noonan syndromeInheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
- Moyamoya diseaseInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary pheochromocytoma-paragangliomaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial ovarian cancerInheritance: Unknown 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 22 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PS3
PS3 evidence extracted from ClinVar submissions: SCV007097379: Classified as Pathogenic per ACMG/AMP criteria (PVS1, PM2, PS3_supporting).
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-31338733-CACTT-C is Pathogenic according to our data. Variant chr17-31338733-CACTT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 216866.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.
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| NF1 | TSL:1 MANE Select | c.6852_6855delTTAC | p.Tyr2285ThrfsTer5 | frameshift | Exon 46 of 58 | ENSP00000351015.4 | P21359-1 | ||
| NF1 | TSL:1 | c.6789_6792delTTAC | p.Tyr2264ThrfsTer5 | frameshift | Exon 45 of 57 | ENSP00000348498.3 | P21359-2 | ||
| NF1 | TSL:1 | n.*2017_*2020delTTAC | non_coding_transcript_exon | Exon 46 of 58 | ENSP00000462408.2 | J3KSB5 |
Frequencies
GnomAD3 genomes 0.00 AC: 0AN: 152128Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
0
AN:
152128
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1460962Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 726830 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1460962
Hom.:
AF XY:
AC XY:
1
AN XY:
726830
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33450
American (AMR)
AF:
AC:
0
AN:
44716
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26102
East Asian (EAS)
AF:
AC:
0
AN:
39556
South Asian (SAS)
AF:
AC:
0
AN:
86220
European-Finnish (FIN)
AF:
AC:
0
AN:
53396
Middle Eastern (MID)
AF:
AC:
0
AN:
5760
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1111420
Other (OTH)
AF:
AC:
1
AN:
60342
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome 0.00 AC: 0AN: 152128Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74306
GnomAD4 genome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
AC:
0
AN:
152128
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
74306
African (AFR)
AF:
AC:
0
AN:
41432
American (AMR)
AF:
AC:
0
AN:
15260
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3472
East Asian (EAS)
AF:
AC:
0
AN:
5208
South Asian (SAS)
AF:
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
AC:
0
AN:
10594
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
0
AN:
68008
Other (OTH)
AF:
AC:
0
AN:
2094
Alfa
AF:
Hom.:
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
11
-
-
Neurofibromatosis, type 1 (11)
5
-
-
not provided (5)
1
-
-
Hereditary cancer-predisposing syndrome (1)
1
-
-
Juvenile myelomonocytic leukemia (1)
1
-
-
Neurofibromatosis-Noonan syndrome (1)
-
-
-
Embryonal rhabdomyosarcoma (1)
-
-
-
Ganglioglioma (1)
-
-
-
Neoplasm (1)
-
-
-
Neuroepithelial neoplasm (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
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
You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.