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rs149739570

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP2BP4_ModerateBP6BS2_Supporting

The NM_001042492.3(NF1):c.1166A>G(p.His389Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000106 in 1,613,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H389H) has been classified as Likely benign.

Frequency

Genomes: đť‘“ 0.000066 ( 0 hom., cov: 32)
Exomes đť‘“: 0.00011 ( 0 hom. )

Consequence

NF1
NM_001042492.3 missense

Scores

1
2
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:6B:6

Conservation

PhyloP100: 7.10
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_001042492.3
PP2
Missense variant where missense usually causes diseases, NF1
BP4
Computational evidence support a benign effect (MetaRNN=0.2315459).
BP6
Variant 17-31201140-A-G is Benign according to our data. Variant chr17-31201140-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141982.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=6}. Variant chr17-31201140-A-G is described in Lovd as [Benign].
BS2
High AC in GnomAd4 at 10 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NF1NM_001042492.3 linkuse as main transcriptc.1166A>G p.His389Arg missense_variant 10/58 ENST00000358273.9
NF1NM_000267.3 linkuse as main transcriptc.1166A>G p.His389Arg missense_variant 10/57
NF1NM_001128147.3 linkuse as main transcriptc.1166A>G p.His389Arg missense_variant 10/15

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NF1ENST00000358273.9 linkuse as main transcriptc.1166A>G p.His389Arg missense_variant 10/581 NM_001042492.3 P1P21359-1

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152192
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000796
AC:
20
AN:
251370
Hom.:
0
AF XY:
0.0000662
AC XY:
9
AN XY:
135854
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000110
AC:
161
AN:
1461798
Hom.:
0
Cov.:
32
AF XY:
0.000106
AC XY:
77
AN XY:
727190
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000141
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152192
Hom.:
0
Cov.:
32
AF XY:
0.0000672
AC XY:
5
AN XY:
74360
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000148
Hom.:
0
Bravo
AF:
0.000136
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000659
AC:
8
EpiCase
AF:
0.000164
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:6Benign:6
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitterclinical testingGeneKor MSAAug 01, 2018- -
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJul 13, 2023This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submittercurationSema4, Sema4May 20, 2020- -
Neurofibromatosis, type 1;C0349639:Juvenile myelomonocytic leukemia;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoAug 11, 2021NF1 NM_000267.3 exon 10 p.His389Arg (c.1166A>G): This variant has been reported in the literature in at least 2 individuals: 1 individual with clinical suspicion of Neurofibromatosis-1 (NF1) and 1 individual with NF1; of note, this individual was reported to have a second, truncating NF1 variant (Warejko 2018 PMID:29483232; Kluwe 2021 PMID:33231931). This variant is present in 0.01% (10/68020) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/17-31201140-A-G?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:141982). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Neurofibromatosis, type 1 Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeJan 28, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Atypical coarctation of aorta Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyYale Center for Mendelian Genomics, Yale UniversityFeb 26, 2018- -
Neurofibromatosis, familial spinal Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Café-au-lait macules with pulmonary stenosis Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Neurofibromatosis-Noonan syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxJan 04, 2021In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with a personal or family history including midaortic syndrome (Warejko 2018); This variant is associated with the following publications: (PMID: 33231931, 28550306, 28380455, 29483232, 31159747) -
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMay 08, 2019This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.14
CADD
Benign
22
DANN
Benign
0.90
Eigen
Benign
-0.039
Eigen_PC
Benign
0.17
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.78
T;T;T;T;T
M_CAP
Uncertain
0.13
D
MetaRNN
Benign
0.23
T;T;T;T;T
MetaSVM
Benign
-0.52
T
MutationAssessor
Benign
1.0
L;L;L;L;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.76
T
Polyphen
0.0
B;B;B;.;.
Vest4
0.53, 0.49, 0.33
MVP
0.74
MPC
0.84
ClinPred
0.18
T
GERP RS
5.5
Varity_R
0.50
gMVP
0.51

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs149739570; hg19: chr17-29528158; COSMIC: COSV100646426; API