rs2066736

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001042492.3(NF1):c.3496+33C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,612,700 control chromosomes in the GnomAD database, including 93,276 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 13872 hom., cov: 31)

Exomes 𝑓: 0.32 ( 79404 hom. )

Consequence

NF1
NM_001042492.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.204

Publications

19 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 17-31232914-C-A is Benign according to our data. Variant chr17-31232914-C-A is described in ClinVar as Benign. ClinVar VariationId is 257285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.605 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3 link	c.3496+33C>A		intron_variant	Intron 26 of 57	ENST00000358273.9	NP_001035957.1	P21359-1
NF1	NM_000267.4 link	c.3496+33C>A		intron_variant	Intron 26 of 56		NP_000258.1	P21359-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 link	c.3496+33C>A		intron_variant	Intron 26 of 57	1	NM_001042492.3	ENSP00000351015.4		P21359-1

Frequencies

GnomAD3 genomes

AF:

0.404

AC:

61271

AN:

151822

Hom.:

13847

Cov.:

show subpopulations

Gnomad AFR

AF:

0.611

Gnomad AMI

AF:

0.280

Gnomad AMR

AF:

0.426

Gnomad ASJ

AF:

0.232

Gnomad EAS

AF:

0.438

Gnomad SAS

AF:

0.372

Gnomad FIN

AF:

0.344

Gnomad MID

AF:

0.203

Gnomad NFE

AF:

0.294

Gnomad OTH

AF:

0.344

GnomAD2 exomes

AF:

0.365

AC:

91091

AN:

249686

AF XY:

0.351

show subpopulations

Gnomad AFR exome

AF:

0.616

Gnomad AMR exome

AF:

0.486

Gnomad ASJ exome

AF:

0.223

Gnomad EAS exome

AF:

0.437

Gnomad FIN exome

AF:

0.340

Gnomad NFE exome

AF:

0.300

Gnomad OTH exome

AF:

0.324

GnomAD4 exome

AF:

0.322

AC:

469868

AN:

1460760

Hom.:

79404

Cov.:

AF XY:

0.321

AC XY:

233103

AN XY:

726724

show subpopulations

African (AFR)

AF:

0.622

AC:

20802

AN:

33436

American (AMR)

AF:

0.477

AC:

21292

AN:

44596

Ashkenazi Jewish (ASJ)

AF:

0.225

AC:

5876

AN:

26118

East Asian (EAS)

AF:

0.444

AC:

17615

AN:

39648

South Asian (SAS)

AF:

0.363

AC:

31255

AN:

86184

European-Finnish (FIN)

AF:

0.344

AC:

18385

AN:

53376

Middle Eastern (MID)

AF:

0.219

AC:

1260

AN:

5764

European-Non Finnish (NFE)

AF:

0.300

AC:

333806

AN:

1111286

Other (OTH)

AF:

0.324

AC:

19577

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

16563

33125

49688

66250

82813

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11288

22576

33864

45152

56440

<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:

0.404

AC:

61346

AN:

151940

Hom.:

13872

Cov.:

AF XY:

0.408

AC XY:

30275

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.611

AC:

25291

AN:

41406

American (AMR)

AF:

0.426

AC:

6510

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.232

AC:

804

AN:

3466

East Asian (EAS)

AF:

0.439

AC:

2270

AN:

5170

South Asian (SAS)

AF:

0.374

AC:

1793

AN:

4796

European-Finnish (FIN)

AF:

0.344

AC:

3633

AN:

10548

Middle Eastern (MID)

AF:

0.204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.294

AC:

20005

AN:

67960

Other (OTH)

AF:

0.343

AC:

725

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1712

3423

5135

6846

8558

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

566

1132

1698

2264

2830

<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:

0.252

Hom.:

920

Bravo

AF:

0.417

Asia WGS

AF:

0.416

AC:

1448

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 10, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neurofibromatosis, type 1

Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jun 23, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Neurofibromatosis, familial spinal

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.0

(source)

DANN

Benign

0.61

PhyloP100

0.20

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over