NM_001042492.3:c.499_502delTGTT
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001042492.3(NF1):c.499_502delTGTT(p.Cys167GlnfsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,702 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: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
NF1
NM_001042492.3 frameshift
NM_001042492.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.72
Publications
15 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
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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 17-31169905-CTGTT-C is Pathogenic according to our data. Variant chr17-31169905-CTGTT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 185021.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
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| NF1 | NM_001042492.3 | MANE Select | c.499_502delTGTT | p.Cys167GlnfsTer10 | frameshift | Exon 5 of 58 | NP_001035957.1 | ||
| NF1 | NM_000267.4 | c.499_502delTGTT | p.Cys167GlnfsTer10 | frameshift | Exon 5 of 57 | NP_000258.1 | |||
| NF1 | NM_001128147.3 | c.499_502delTGTT | p.Cys167GlnfsTer10 | frameshift | Exon 5 of 15 | NP_001121619.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| NF1 | ENST00000358273.9 | TSL:1 MANE Select | c.499_502delTGTT | p.Cys167GlnfsTer10 | frameshift | Exon 5 of 58 | ENSP00000351015.4 | ||
| NF1 | ENST00000356175.7 | TSL:1 | c.499_502delTGTT | p.Cys167GlnfsTer10 | frameshift | Exon 5 of 57 | ENSP00000348498.3 | ||
| NF1 | ENST00000431387.8 | TSL:1 | c.499_502delTGTT | p.Cys167GlnfsTer10 | frameshift | Exon 5 of 15 | ENSP00000412921.4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD2 exomes AF: 0.00000398 AC: 1AN: 251028 AF XY: 0.00000737 show subpopulations
GnomAD2 exomes
AF:
AC:
1
AN:
251028
AF XY:
Gnomad AFR exome
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Gnomad AMR exome
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Gnomad ASJ exome
AF:
Gnomad EAS exome
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Gnomad FIN exome
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Gnomad NFE exome
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Gnomad OTH exome
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GnomAD4 exome AF: 6.93e-7 AC: 1AN: 1442702Hom.: 0 AF XY: 0.00000139 AC XY: 1AN XY: 718206 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1442702
Hom.:
AF XY:
AC XY:
1
AN XY:
718206
show subpopulations
African (AFR)
AF:
AC:
0
AN:
32748
American (AMR)
AF:
AC:
1
AN:
44196
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25386
East Asian (EAS)
AF:
AC:
0
AN:
38112
South Asian (SAS)
AF:
AC:
0
AN:
86030
European-Finnish (FIN)
AF:
AC:
0
AN:
51596
Middle Eastern (MID)
AF:
AC:
0
AN:
5582
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1100018
Other (OTH)
AF:
AC:
0
AN:
59034
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
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2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
32
Alfa
AF:
Hom.:
ClinVar
ClinVar submissions as Germline
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts