rs587781755

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1PP2BS2_Supporting

The NM_001042492.3(NF1):c.4219A>G(p.Ser1407Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,461,710 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

NF1
NM_001042492.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:10

Conservation

PhyloP100: 8.91

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 2 ACMG points.

PM1

In a helix (size 10) in uniprot entity NF1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001042492.3

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.

BS2

High AC in GnomAdExome4 at 25 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.4219A>G	p.Ser1407Gly	missense_variant	32/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3 linkuse as main transcript	c.4156A>G	p.Ser1386Gly	missense_variant	31/57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 linkuse as main transcript	c.4219A>G	p.Ser1407Gly	missense_variant	32/58	1	NM_001042492.3	ENSP00000351015	P1	P21359-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251250

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135780

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461710

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727154

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:

0.0000225

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000659

Hom.:

Bravo

AF:

0.00000756

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurofibromatosis, type 1

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PP3. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 12, 2023	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 1386 of the NF1 protein (p.Ser1386Gly). This variant is present in population databases (rs587781755, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 141448). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NF1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 22, 2015	The p.S1407G variant (also known as c.4219A>G), located in coding exon 32 of the NF1 gene, results from an A to G substitution at nucleotide position 4219. The serine at codon 1407 is replaced by glycine, an amino acid with some similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. <span style="background-color:initial">To date, this alteration has been detected with an allele frequency of approximately 0.004% (greater than 110000 alleles tested) in our clinical cohort.<span style="background-color:initial">This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging and deleterious by PolyPhen and SIFT in silico<span style="background-color:initial"> analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.S1407G remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 15, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 07, 2020

DNA sequence analysis of the NF1 gene demonstrated a sequence change, c.4156A>G, in exon 31 that results in an amino acid change, p.Ser1386Gly. 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 0.00040% (dbSNP rs587781755). The p.Ser1386Gly 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.Ser1386Gly substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ser1386Gly change remains unknown at this time. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 11, 2021

- -

Juvenile myelomonocytic leukemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 30, 2023

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 21, 2023

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with severe bilateral ventriculomegaly, aqueductal stenosis, gray matter heterotopia, and polyhydramnios (Tolusso et al., 2021); Observed in cases and controls in a breast cancer case-control study (Dorling et al., 2021); Also known as 4219A>G; This variant is associated with the following publications: (PMID: 25486365, 22807134, 33442022, 33471991) -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 02, 2022

The c.4156A>G (p.S1386G) alteration is located in exon 31 (coding exon 31) of the NF1 gene. This alteration results from a A to G substitution at nucleotide position 4156, causing the serine (S) at amino acid position 1386 to be replaced by a glycine (G). 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

0.71

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

D;.;D

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Pathogenic

0.69

MetaRNN

Uncertain

0.73

D;D;D

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

0.64

N;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-2.7

D;D;D

REVEL

Uncertain

0.64

Sift

Benign

0.18

T;T;T

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

0.88

P;P;.

Vest4

0.89

MVP

0.85

MPC

1.6

ClinPred

0.85

GERP RS

5.9

Varity_R

0.80

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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