Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001042492.3(NF1):c.846G>A(p.Gln282Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00366 in 1,613,864 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0038 ( 89 hom. )

Consequence

NF1
NM_001042492.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24

Conservation

PhyloP100: 0.844

Publications

12 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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 17-31182623-G-A is Benign according to our data. Variant chr17-31182623-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 184123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.844 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00236 (359/152298) while in subpopulation SAS AF = 0.0286 (138/4824). AF 95% confidence interval is 0.0247. There are 1 homozygotes in GnomAd4. There are 209 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 359 AD gene.

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.846G>A	p.Gln282Gln	synonymous	Exon 8 of 58	NP_001035957.1
NF1	NM_000267.4		c.846G>A	p.Gln282Gln	synonymous	Exon 8 of 57	NP_000258.1
NF1	NM_001128147.3		c.846G>A	p.Gln282Gln	synonymous	Exon 8 of 15	NP_001121619.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NF1	ENST00000358273.9	TSL:1 MANE Select	c.846G>A	p.Gln282Gln	synonymous	Exon 8 of 58	ENSP00000351015.4
NF1	ENST00000356175.7	TSL:1	c.846G>A	p.Gln282Gln	synonymous	Exon 8 of 57	ENSP00000348498.3
NF1	ENST00000431387.8	TSL:1	c.846G>A	p.Gln282Gln	synonymous	Exon 8 of 15	ENSP00000412921.4

Frequencies

GnomAD3 genomes

AF:

0.00237

AC:

360

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0288

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00210

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00548

AC:

1374

AN:

250938

AF XY:

0.00700

show subpopulations

Gnomad AFR exome

AF:

0.000616

Gnomad AMR exome

AF:

0.000782

Gnomad ASJ exome

AF:

0.00884

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.000324

Gnomad NFE exome

AF:

0.00196

Gnomad OTH exome

AF:

0.00441

GnomAD4 exome

AF:

0.00379

AC:

5543

AN:

1461566

Hom.:

Cov.:

AF XY:

0.00482

AC XY:

3507

AN XY:

727068

show subpopulations

African (AFR)

AF:

0.000358

AC:

AN:

33476

American (AMR)

AF:

0.000805

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00903

AC:

236

AN:

26124

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39678

South Asian (SAS)

AF:

0.0329

AC:

2834

AN:

86200

European-Finnish (FIN)

AF:

0.000225

AC:

AN:

53376

Middle Eastern (MID)

AF:

0.0156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00184

AC:

2042

AN:

1111862

Other (OTH)

AF:

0.00462

AC:

279

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

303

607

910

1214

1517

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

200

300

400

500

<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:

0.00236

AC:

359

AN:

152298

Hom.:

Cov.:

AF XY:

0.00281

AC XY:

209

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41554

American (AMR)

AF:

0.00150

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00720

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.0286

AC:

138

AN:

4824

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00210

AC:

143

AN:

68032

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

105

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00250

Hom.:

Bravo

AF:

0.00164

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

Neurofibromatosis, type 1 (6)

not specified (4)

Neurofibromatosis, familial spinal (2)

Café-au-lait macules with pulmonary stenosis (1)

Hereditary cancer-predisposing syndrome (1)

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

Myopathy, centronuclear, 5 (1)

Neurofibromatosis-Noonan syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

6.5

(source)

DANN

Benign

0.68

PhyloP100

0.84

Mutation Taster

=100/0

polymorphism

(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

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over