rs368685980

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PP2PP3BS2_Supporting

The NM_001042492.3(NF1):c.4187G>A(p.Arg1396His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,613,572 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 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

NF1
NM_001042492.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.56

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 3 ACMG points.

PM1

In a domain Ras-GAP (size 216) in uniprot entity NF1_HUMAN there are 42 pathogenic changes around while only 3 benign (93%) in NM_001042492.3

PP2

Missense variant in the NF1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 399 curated pathogenic missense variants (we use a threshold of 10). The gene has 143 curated benign missense variants. Gene score misZ: 6.5427 (above the threshold of 3.09). Trascript score misZ: 8.4054 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.819

BS2

High AC in GnomAdExome4 at 30 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 rank	MANE	Protein	UniProt
NF1	NM_001042492.3 link	c.4187G>A	p.Arg1396His	missense_variant	Exon 32 of 58	ENST00000358273.9	NP_001035957.1	P21359-1
NF1	NM_000267.3 link	c.4124G>A	p.Arg1375His	missense_variant	Exon 31 of 57		NP_000258.1	P21359-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 link	c.4187G>A	p.Arg1396His	missense_variant	Exon 32 of 58	1	NM_001042492.3	ENSP00000351015.4		P21359-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151920

Hom.:

Cov.:

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251244

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135784

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:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461652

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727136

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151920

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74194

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Neurofibromatosis, type 1

Uncertain:1Benign:1

Mar 15, 2022

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurofibromatosis, type 1;C0349639:Juvenile myelomonocytic leukemia;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome

Uncertain:1

May 06, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NF1: PM2, PP3 -

Juvenile myelomonocytic leukemia

Uncertain:1

Feb 19, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Uncertain:1

Nov 22, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4124G>A (p.R1375H) alteration is located in exon 31 (coding exon 31) of the NF1 gene. This alteration results from a G to A substitution at nucleotide position 4124, causing the arginine (R) at amino acid position 1375 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.89

D;.;D

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.82

D;D;D

MetaSVM

Uncertain

0.47

MutationAssessor

Uncertain

2.1

M;.;.

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-3.3

D;D;D

REVEL

Uncertain

0.60

Sift

Uncertain

0.0010

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.91

MVP

0.95

MPC

1.9

ClinPred

0.98

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.80

gMVP

0.63

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