rs587782686

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM1BS2_Supporting

The NM_001042492.3(NF1):c.83A>C(p.Gln28Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,613,436 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q28Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

NF1
NM_001042492.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:1

Conservation

PhyloP100: 8.78

Publications

4 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 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 6 benign, 35 uncertain in NM_001042492.3

BS2

High AC in GnomAdExome4 at 32 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.83A>C	p.Gln28Pro	missense_variant	Exon 2 of 58	ENST00000358273.9	NP_001035957.1	P21359-1
NF1	NM_000267.4 link	c.83A>C	p.Gln28Pro	missense_variant	Exon 2 of 57		NP_000258.1	P21359-2
NF1	NM_001128147.3 link	c.83A>C	p.Gln28Pro	missense_variant	Exon 2 of 15		NP_001121619.1	P21359-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 link	c.83A>C	p.Gln28Pro	missense_variant	Exon 2 of 58	1	NM_001042492.3	ENSP00000351015.4		P21359-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151984

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

250968

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:

0.0000219

AC:

AN:

1461452

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727020

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39604

South Asian (SAS)

AF:

0.00

AC:

AN:

86190

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000270

AC:

AN:

1111824

Other (OTH)

AF:

0.0000331

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151984

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41374

American (AMR)

AF:

0.00

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10566

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67990

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Apr 08, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in individuals with breast cancer as well as unaffected controls (PMID: 33471991); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33471991, 30476936) -

Hereditary cancer-predisposing syndrome

Uncertain:2

Mar 09, 2022

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Sep 17, 2015

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ã¢â‚¬â€¹The p.Q28P variant (also known as c.83A>C), located in coding exon 2 of the NF1 gene, results from an A to C substitution at nucleotide position 83. The glutamine at codon 28 is replaced by proline, an amino acid with 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. This amino acid position is highly conserved in available vertebrate species. To date, this alteration has been detected with an allele frequency of approximately 0.003% (greater than 110000 alleles tested) in our clinical cohort. In addition, this alteration is predicted to be possibly damaging yet tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.Q28P remains unclear. -

Neurofibromatosis, type 1

Uncertain:1Benign:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 15, 2022

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Feb 02, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: NF1 c.83A>C (p.Gln28Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250968 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.83A>C in individuals affected with Neurofibromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

NF1-related disorder

Uncertain:1

Feb 22, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The NF1 c.83A>C variant is predicted to result in the amino acid substitution p.Gln28Pro. This variant was reported in an individual with breast cancer as well as in two unaffected controls (Breast Cancer Association Consortium et al. 2021. PubMed ID: 33471991). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142742/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Jun 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Uncertain:1

Apr 05, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.83A>C (p.Q28P) alteration is located in exon 2 (coding exon 2) of the NF1 gene. This alteration results from a A to C substitution at nucleotide position 83, causing the glutamine (Q) at amino acid position 28 to be replaced by a proline (P). 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

Benign

0.13

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.70

.;D;.;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Pathogenic

0.42

MetaRNN

Uncertain

0.63

D;D;D;D

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.3

M;M;M;M

PhyloP100

8.8

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-2.7

.;D;D;D

REVEL

Uncertain

0.35

Sift

Benign

0.15

.;T;T;T

Sift4G

Uncertain

0.034

.;D;D;D

Polyphen

0.96

D;D;P;.

Vest4

0.88, 0.89, 0.81

MVP

0.85

MPC

1.8

ClinPred

0.91

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.44

gMVP

0.70

Mutation Taster

=20/80

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over