17-31260464-G-A

Position:

chr17-31260464-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PP2PP3_ModerateBP6BS2_Supporting

The NM_001042492.3(NF1):c.4526G>A(p.Arg1509His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000075 in 1,613,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

NF1
NM_001042492.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:5O:1

Conservation

PhyloP100: 9.25

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NF1. . Gene score misZ 6.5427 (greater than the threshold 3.09). Trascript score misZ 8.4054 (greater than threshold 3.09). GenCC has associacion of gene with neurofibromatosis, familial spinal, hereditary pheochromocytoma-paraganglioma, neurofibromatosis type 1, Watson syndrome, neurofibromatosis-Noonan syndrome, Moyamoya disease, familial ovarian cancer.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.87

BP6

Variant 17-31260464-G-A is Benign according to our data. Variant chr17-31260464-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141323.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, not_provided=1, Uncertain_significance=4}.

BS2

High AC in GnomAd4 at 9 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	Protein	UniProt
NF1	NM_001042492.3 linkuse as main transcript	c.4526G>A	p.Arg1509His	missense_variant	34/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3 linkuse as main transcript	c.4463G>A	p.Arg1488His	missense_variant	33/57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 linkuse as main transcript	c.4526G>A	p.Arg1509His	missense_variant	34/58	1	NM_001042492.3	ENSP00000351015	P1	P21359-1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000882

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000107

AC:

AN:

251282

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135804

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:

0.0000327

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000766

AC:

112

AN:

1461686

Hom.:

Cov.:

AF XY:

0.0000784

AC XY:

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.000169

Gnomad4 NFE exome

AF:

0.0000809

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152054

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74258

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000559

Hom.:

Bravo

AF:

0.0000302

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000115

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 12, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 05, 2016	in silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Insufficient or Conflicting Evidence -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 29, 2021	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 09, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with cafe-au-lait macules in published literature who had a different genetic etiology for the phenotype (Koczkowska 2018); This variant is associated with the following publications: (PMID: 22675565, 26919320, 29290338, 30613976, 22807134) -

Neurofibromatosis, type 1

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Medical Genetics, University of Parma	Aug 17, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 07, 2021

This sequence change does not appear to have been previously described in patients with NF1-related disorders and has been described in the gnomAD database with a low population frequency of 0.015% in the non-Finnish subpopulation (dbSNP rs546073780). The p.Arg1488His change affects a highly conserved amino acid residue located in a domain of the NF1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg1488His substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg1488His change remains unknown at this time. -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 28, 2020

This 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. -

Neurofibromatosis, type 1;C0553586:Café-au-lait macules with pulmonary stenosis;C2931482:Neurofibromatosis-Noonan syndrome

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

Variant interpreted as Uncertain significance and reported on 11-21-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

D;.;T

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.87

D;D;D

MetaSVM

Uncertain

0.49

MutationAssessor

Uncertain

2.3

M;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.92

PROVEAN

Uncertain

-4.3

D;D;D

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0020

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.94

MutPred

0.55

Loss of helix (P = 0.028);.;.;

MVP

0.98

MPC

1.9

ClinPred

0.73

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.59

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over