rs9894648

Variant names:

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.5268+23T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.621 in 1,599,250 control chromosomes in the GnomAD database, including 312,036 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.65 ( 32442 hom., cov: 32)

Exomes 𝑓: 0.62 ( 279594 hom. )

Consequence

NF1
NM_001042492.3 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.00900

Publications

24 publications found

Variant links:

COSMIC-nc: COSV55985627

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=-0.83).

BP6

Variant 17-31326275-T-C is Benign according to our data. Variant chr17-31326275-T-C is described in ClinVar as Benign. ClinVar VariationId is 257293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.742 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3 link	c.5268+23T>C		intron_variant	Intron 37 of 57	ENST00000358273.9	NP_001035957.1	P21359-1
NF1	NM_000267.4 link	c.5205+23T>C		intron_variant	Intron 36 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.5268+23T>C		intron_variant	Intron 37 of 57	1	NM_001042492.3	ENSP00000351015.4		P21359-1

Frequencies

GnomAD3 genomes

AF:

0.647

AC:

98310

AN:

151888

Hom.:

32416

Cov.:

show subpopulations

Gnomad AFR

AF:

0.749

Gnomad AMI

AF:

0.697

Gnomad AMR

AF:

0.510

Gnomad ASJ

AF:

0.704

Gnomad EAS

AF:

0.447

Gnomad SAS

AF:

0.620

Gnomad FIN

AF:

0.620

Gnomad MID

AF:

0.665

Gnomad NFE

AF:

0.634

Gnomad OTH

AF:

0.651

GnomAD2 exomes

AF:

0.591

AC:

140307

AN:

237330

AF XY:

0.601

show subpopulations

Gnomad AFR exome

AF:

0.753

Gnomad AMR exome

AF:

0.413

Gnomad ASJ exome

AF:

0.704

Gnomad EAS exome

AF:

0.441

Gnomad FIN exome

AF:

0.618

Gnomad NFE exome

AF:

0.625

Gnomad OTH exome

AF:

0.608

GnomAD4 exome

AF:

0.619

AC:

895405

AN:

1447244

Hom.:

279594

Cov.:

AF XY:

0.620

AC XY:

446658

AN XY:

720492

show subpopulations

African (AFR)

AF:

0.759

AC:

25365

AN:

33422

American (AMR)

AF:

0.427

AC:

19069

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.706

AC:

18433

AN:

26120

East Asian (EAS)

AF:

0.473

AC:

18776

AN:

39680

South Asian (SAS)

AF:

0.628

AC:

54163

AN:

86192

European-Finnish (FIN)

AF:

0.610

AC:

25278

AN:

41430

Middle Eastern (MID)

AF:

0.712

AC:

4100

AN:

5762

European-Non Finnish (NFE)

AF:

0.624

AC:

692659

AN:

1109686

Other (OTH)

AF:

0.623

AC:

37562

AN:

60260

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

17478

34957

52435

69914

87392

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18462

36924

55386

73848

92310

<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:

0.647

AC:

98373

AN:

152006

Hom.:

32442

Cov.:

AF XY:

0.642

AC XY:

47685

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.749

AC:

31052

AN:

41448

American (AMR)

AF:

0.510

AC:

7789

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.704

AC:

2445

AN:

3472

East Asian (EAS)

AF:

0.446

AC:

2302

AN:

5164

South Asian (SAS)

AF:

0.618

AC:

2973

AN:

4808

European-Finnish (FIN)

AF:

0.620

AC:

6542

AN:

10544

Middle Eastern (MID)

AF:

0.667

AC:

196

AN:

294

European-Non Finnish (NFE)

AF:

0.634

AC:

43075

AN:

67976

Other (OTH)

AF:

0.647

AC:

1366

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1744

3489

5233

6978

8722

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

790

1580

2370

3160

3950

<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:

0.645

Hom.:

6071

Bravo

AF:

0.643

Asia WGS

AF:

0.527

AC:

1831

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 20, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

-0.83

CADD

Benign

2.3

(source)

DANN

Benign

0.41

PhyloP100

0.0090

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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