NM_001042492.3:c.1466A>G
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_001042492.3(NF1):c.1466A>G(p.Tyr489Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,611,968 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y489S) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
NF1
NM_001042492.3 missense
NM_001042492.3 missense
Scores
3
10
5
Clinical Significance
Conservation
PhyloP100: 6.75
Publications
61 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 12 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 17-31214524-A-G is Pathogenic according to our data. Variant chr17-31214524-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 354.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.1466A>G | p.Tyr489Cys | missense | Exon 13 of 58 | NP_001035957.1 | ||
| NF1 | NM_000267.4 | c.1466A>G | p.Tyr489Cys | missense | Exon 13 of 57 | NP_000258.1 | |||
| NF1 | NM_001128147.3 | c.1466A>G | p.Tyr489Cys | missense | Exon 13 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.1466A>G | p.Tyr489Cys | missense | Exon 13 of 58 | ENSP00000351015.4 | ||
| NF1 | ENST00000356175.7 | TSL:1 | c.1466A>G | p.Tyr489Cys | missense | Exon 13 of 57 | ENSP00000348498.3 | ||
| NF1 | ENST00000431387.8 | TSL:1 | c.1466A>G | p.Tyr489Cys | missense | Exon 13 of 15 | ENSP00000412921.4 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152186Hom.: 0 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
152186
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:
GnomAD2 exomes AF: 0.0000120 AC: 3AN: 250646 AF XY: 0.00000738 show subpopulations
GnomAD2 exomes
AF:
AC:
3
AN:
250646
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1459782Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 726326 show subpopulations
GnomAD4 exome
AF:
AC:
3
AN:
1459782
Hom.:
Cov.:
30
AF XY:
AC XY:
1
AN XY:
726326
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33420
American (AMR)
AF:
AC:
0
AN:
44672
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26096
East Asian (EAS)
AF:
AC:
0
AN:
39544
South Asian (SAS)
AF:
AC:
0
AN:
86164
European-Finnish (FIN)
AF:
AC:
0
AN:
53410
Middle Eastern (MID)
AF:
AC:
0
AN:
5696
European-Non Finnish (NFE)
AF:
AC:
3
AN:
1110490
Other (OTH)
AF:
AC:
0
AN:
60290
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome 0.00000657 AC: 1AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74348 show subpopulations
GnomAD4 genome
AF:
AC:
1
AN:
152186
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
74348
show subpopulations
African (AFR)
AF:
AC:
0
AN:
41460
American (AMR)
AF:
AC:
0
AN:
15278
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3472
East Asian (EAS)
AF:
AC:
0
AN:
5196
South Asian (SAS)
AF:
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
AC:
0
AN:
10606
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
1
AN:
68018
Other (OTH)
AF:
AC:
0
AN:
2092
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
Alfa
AF:
Hom.:
ESP6500AA
AF:
AC:
1
ESP6500EA
AF:
AC:
1
ExAC
AF:
AC:
2
ClinVar
ClinVar submissions as Germline
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts