GeneBe

rs786201874

Variant names:

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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:26O:1

Conservation

PhyloP100: 8.72

Publications

15 publications found
Variant links:
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 1
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
  • neurofibromatosis-Noonan syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
  • Moyamoya disease
    Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
  • hereditary pheochromocytoma-paraganglioma
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • familial ovarian cancer
    Inheritance: 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 17-31169905-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
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
NF1
NM_001042492.3
MANE Select
c.499_502delTGTTp.Cys167GlnfsTer10
frameshift
Exon 5 of 58NP_001035957.1
NF1
NM_000267.4
c.499_502delTGTTp.Cys167GlnfsTer10
frameshift
Exon 5 of 57NP_000258.1
NF1
NM_001128147.3
c.499_502delTGTTp.Cys167GlnfsTer10
frameshift
Exon 5 of 15NP_001121619.1

Ensembl Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
NF1
ENST00000358273.9
TSL:1 MANE Select
c.499_502delTGTTp.Cys167GlnfsTer10
frameshift
Exon 5 of 58ENSP00000351015.4
NF1
ENST00000356175.7
TSL:1
c.499_502delTGTTp.Cys167GlnfsTer10
frameshift
Exon 5 of 57ENSP00000348498.3
NF1
ENST00000431387.8
TSL:1
c.499_502delTGTTp.Cys167GlnfsTer10
frameshift
Exon 5 of 15ENSP00000412921.4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000398
AC:
1
AN:
251028
AF XY:
0.00000737
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.93e-7
AC:
1
AN:
1442702
Hom.:
0
AF XY:
0.00000139
AC XY:
1
AN XY:
718206
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
32748
American (AMR)
AF:
0.0000226
AC:
1
AN:
44196
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25386
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38112
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86030
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51596
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5582
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1100018
Other (OTH)
AF:
0.00
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
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0

ClinVar

ClinVar submissions as Germline
Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
View on ClinVar

Computational scores

Publications

Other links and lift over

dbSNP: rs786201874; hg19: chr17-29496923; COSMIC: COSV62217662; API