17-31226564-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP6

The NM_001042492.3(NF1):c.2131C>T(p.Arg711Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,574 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R711H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NF1
NM_001042492.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1O:1

Conservation

PhyloP100: 2.88

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

neurofibromatosis type 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
neurofibromatosis-Noonan syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
Moyamoya disease
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
hereditary pheochromocytoma-paraganglioma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

NF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 24 uncertain in NM_001042492.3

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 17-31226564-C-T is Benign according to our data. Variant chr17-31226564-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 457565.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3 link	c.2131C>T	p.Arg711Cys	missense_variant	Exon 18 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4 link	c.2131C>T	p.Arg711Cys	missense_variant	Exon 18 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 link	c.2131C>T	p.Arg711Cys	missense_variant	Exon 18 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251030

AF XY:

0.00000737

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461574

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727102

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111776

Other (OTH)

AF:

0.00

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1Other: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

- -

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Feb 14, 2018

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is denoted NF1 c.2131C>T at the cDNA level, p.Arg711Cys (R711C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in melanoma and prostate tumors (Hovelson 2015, de Unamuno Bustos 2017). NF1 Arg711Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the GTPase activating protein domain (Luo 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether NF1 Arg711Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Uncertain:1

Jan 03, 2019

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2131C>T (p.R711C) alteration is located in exon 18 (coding exon 18) of the NF1 gene. This alteration results from a C to T substitution at nucleotide position 2131, causing the arginine (R) at amino acid position 711 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Other:1

GenomeConnect - Invitae Patient Insights Network

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Uncertain significance and reported on 04-23-2018 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

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

D;.;T

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.86

LIST_S2

Pathogenic

0.97

D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.69

D;D;D

MetaSVM

Benign

-0.55

MutationAssessor

Benign

1.8

L;L;.

PhyloP100

2.9

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-3.9

D;D;D

REVEL

Uncertain

0.33

Sift

Benign

0.050

D;T;D

Sift4G

Benign

0.085

T;T;T

Polyphen

1.0

D;B;.

Vest4

0.41

MutPred

0.56

Gain of loop (P = 0.0312);Gain of loop (P = 0.0312);.;

MVP

0.95

MPC

1.9

ClinPred

0.98

GERP RS

4.6

Varity_R

0.23

gMVP

0.80

Mutation Taster

=47/53

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over