Genetic Variant NM_001042492.3:c.47G>A (chr17-31095356-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_001042492.3(NF1):c.47G>A(p.Arg16His) variant causes a missense change. The variant allele was found at a frequency of 0.000000721 in 1,387,694 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R16G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

NF1
NM_001042492.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.84

Publications

0 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 4 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain in NM_001042492.3

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3 link	c.47G>A	p.Arg16His	missense_variant	Exon 1 of 58	ENST00000358273.9	NP_001035957.1	P21359-1
NF1	NM_000267.4 link	c.47G>A	p.Arg16His	missense_variant	Exon 1 of 57		NP_000258.1	P21359-2
NF1	NM_001128147.3 link	c.47G>A	p.Arg16His	missense_variant	Exon 1 of 15		NP_001121619.1	P21359-5
MIR4733HG	NR_186435.1 link	n.135C>T		non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 link	c.47G>A	p.Arg16His	missense_variant	Exon 1 of 58	1	NM_001042492.3	ENSP00000351015.4		P21359-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.21e-7

AC:

AN:

1387694

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

684770

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31578

American (AMR)

AF:

0.00

AC:

AN:

35658

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25116

East Asian (EAS)

AF:

0.00

AC:

AN:

35890

South Asian (SAS)

AF:

0.00

AC:

AN:

79154

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39858

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4168

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078538

Other (OTH)

AF:

0.0000173

AC:

AN:

57734

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

.;D;.;.

Eigen

Uncertain

0.36

Eigen_PC

Benign

0.22

FATHMM_MKL

Benign

0.45

LIST_S2

Uncertain

0.91

D;D;D;D

M_CAP

Pathogenic

0.79

MetaRNN

Uncertain

0.46

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

M;M;M;M

PhyloP100

3.8

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-2.8

.;D;D;D

REVEL

Benign

0.25

Sift

Pathogenic

0.0

.;D;D;D

Sift4G

Pathogenic

0.0

.;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.41, 0.41, 0.28

MutPred

0.45

Loss of MoRF binding (P = 0.0504);Loss of MoRF binding (P = 0.0504);Loss of MoRF binding (P = 0.0504);Loss of MoRF binding (P = 0.0504);

MVP

0.72

MPC

0.85

ClinPred

0.99

GERP RS

1.7

PromoterAI

0.025

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.50

gMVP

0.81

Mutation Taster

=45/55

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over