Genetic Variant NF1:p.Pro6Arg (chr17-31095326-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001042492.3(NF1):c.17C>G(p.Pro6Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000721 in 1,386,648 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P6L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

NF1
NM_001042492.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 2.87

Publications

5 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 links:

MIR4733HG (HGNC:55332): (MIR4733 host gene)

MIR4733HG links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042492.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NF1	NM_001042492.3	MANE Select	c.17C>G	p.Pro6Arg	missense	Exon 1 of 58	NP_001035957.1
NF1	NM_000267.4		c.17C>G	p.Pro6Arg	missense	Exon 1 of 57	NP_000258.1
NF1	NM_001128147.3		c.17C>G	p.Pro6Arg	missense	Exon 1 of 15	NP_001121619.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NF1	ENST00000358273.9	TSL:1 MANE Select	c.17C>G	p.Pro6Arg	missense	Exon 1 of 58	ENSP00000351015.4
NF1	ENST00000356175.7	TSL:1	c.17C>G	p.Pro6Arg	missense	Exon 1 of 57	ENSP00000348498.3
NF1	ENST00000431387.8	TSL:1	c.17C>G	p.Pro6Arg	missense	Exon 1 of 15	ENSP00000412921.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000742

AC:

AN:

134804

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000409

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.21e-7

AC:

AN:

1386648

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

684136

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31532

American (AMR)

AF:

0.0000281

AC:

AN:

35636

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25136

East Asian (EAS)

AF:

0.00

AC:

AN:

35780

South Asian (SAS)

AF:

0.00

AC:

AN:

79112

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4118

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078274

Other (OTH)

AF:

0.00

AC:

AN:

57712

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neurofibromatosis, type 1 (2)

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Benign

0.61

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.94

MetaRNN

Uncertain

0.48

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.5

PhyloP100

2.9

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-5.0

REVEL

Benign

0.22

Sift

Uncertain

0.0050

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.20

MutPred

0.35

Gain of MoRF binding (P = 2e-04)

MVP

0.54

MPC

0.80

ClinPred

0.99

GERP RS

2.6

PromoterAI

-0.11

Neutral

(source)

Varity_R

0.65

gMVP

0.98

Mutation Taster

=25/75

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over