chr17-31232092-A-G

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.3217A>G(p.Met1073Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000038 in 1,445,932 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. M1073L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000052 ( 0 hom., cov: 27)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

NF1
NM_001042492.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1O:1

Conservation

PhyloP100: 8.85

Publications

5 publications found

Variant links:

COSMIC-nc: COSV62200209

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 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 28 uncertain in NM_001042492.3

BS2

High AC in GnomAd4 at 7 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	NM_001042492.3	MANE Select	c.3217A>G	p.Met1073Val	missense	Exon 25 of 58	NP_001035957.1
	NF1	NM_000267.4		c.3217A>G	p.Met1073Val	missense	Exon 25 of 57	NP_000258.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NF1	ENST00000358273.9	TSL:1 MANE Select	c.3217A>G	p.Met1073Val	missense	Exon 25 of 58	ENSP00000351015.4
NF1	ENST00000356175.7	TSL:1	c.3217A>G	p.Met1073Val	missense	Exon 25 of 57	ENSP00000348498.3
NF1	ENST00000579081.6	TSL:1	n.3217A>G		non_coding_transcript_exon	Exon 25 of 58	ENSP00000462408.2

Frequencies

GnomAD3 genomes

AF:

0.0000521

AC:

AN:

134240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000288

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:

0.0000917

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000125

AC:

AN:

240800

AF XY:

0.0000154

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:

0.0000276

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000366

AC:

AN:

1311626

Hom.:

Cov.:

AF XY:

0.0000319

AC XY:

AN XY:

657452

show subpopulations

African (AFR)

AF:

0.0000332

AC:

AN:

30118

American (AMR)

AF:

0.00

AC:

AN:

42750

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24234

East Asian (EAS)

AF:

0.00

AC:

AN:

37500

South Asian (SAS)

AF:

0.00

AC:

AN:

80322

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51516

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4280

European-Non Finnish (NFE)

AF:

0.0000456

AC:

AN:

986594

Other (OTH)

AF:

0.0000368

AC:

AN:

54312

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

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:

0.0000521

AC:

AN:

134306

Hom.:

Cov.:

AF XY:

0.0000469

AC XY:

AN XY:

63968

show subpopulations

African (AFR)

AF:

0.0000287

AC:

AN:

34862

American (AMR)

AF:

0.00

AC:

AN:

11886

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3392

East Asian (EAS)

AF:

0.00

AC:

AN:

4486

South Asian (SAS)

AF:

0.00

AC:

AN:

4204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7104

Middle Eastern (MID)

AF:

0.00

AC:

AN:

246

European-Non Finnish (NFE)

AF:

0.0000917

AC:

AN:

65418

Other (OTH)

AF:

0.00

AC:

AN:

1810

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000474

Hom.:

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neurofibromatosis, type 1 (2)

not provided (3)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.80

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.71

MetaRNN

Uncertain

0.56

MetaSVM

Benign

-1.2

MutationAssessor

Benign

2.0

PhyloP100

8.8

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.54

Sift

Benign

0.040

Sift4G

Benign

0.21

Polyphen

0.063

Vest4

0.86

MVP

0.89

MPC

0.71

ClinPred

0.69

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.33

gMVP

0.75

Mutation Taster

=2/98

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over