rs964288

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.7458-29G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 1,604,790 control chromosomes in the GnomAD database, including 278,373 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.50 ( 20795 hom., cov: 30)

Exomes 𝑓: 0.59 ( 257578 hom. )

Consequence

NF1
NM_001042492.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.23

Publications

23 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

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 17-31352228-G-A is Benign according to our data. Variant chr17-31352228-G-A is described in ClinVar as Benign. ClinVar VariationId is 257303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.615 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3 link	c.7458-29G>A		intron_variant	Intron 50 of 57	ENST00000358273.9	NP_001035957.1	P21359-1
NF1	NM_000267.4 link	c.7395-29G>A		intron_variant	Intron 49 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.7458-29G>A		intron_variant	Intron 50 of 57	1	NM_001042492.3	ENSP00000351015.4		P21359-1

Frequencies

GnomAD3 genomes

AF:

0.501

AC:

75980

AN:

151750

Hom.:

20787

Cov.:

show subpopulations

Gnomad AFR

AF:

0.287

Gnomad AMI

AF:

0.677

Gnomad AMR

AF:

0.446

Gnomad ASJ

AF:

0.684

Gnomad EAS

AF:

0.356

Gnomad SAS

AF:

0.568

Gnomad FIN

AF:

0.600

Gnomad MID

AF:

0.601

Gnomad NFE

AF:

0.620

Gnomad OTH

AF:

0.532

GnomAD2 exomes

AF:

0.535

AC:

133828

AN:

250220

AF XY:

0.552

show subpopulations

Gnomad AFR exome

AF:

0.276

Gnomad AMR exome

AF:

0.376

Gnomad ASJ exome

AF:

0.686

Gnomad EAS exome

AF:

0.354

Gnomad FIN exome

AF:

0.600

Gnomad NFE exome

AF:

0.611

Gnomad OTH exome

AF:

0.568

GnomAD4 exome

AF:

0.589

AC:

856432

AN:

1452922

Hom.:

257578

Cov.:

AF XY:

0.591

AC XY:

427847

AN XY:

723354

show subpopulations

African (AFR)

AF:

0.272

AC:

9072

AN:

33354

American (AMR)

AF:

0.387

AC:

17292

AN:

44638

Ashkenazi Jewish (ASJ)

AF:

0.688

AC:

17920

AN:

26064

East Asian (EAS)

AF:

0.374

AC:

14814

AN:

39634

South Asian (SAS)

AF:

0.579

AC:

49829

AN:

86000

European-Finnish (FIN)

AF:

0.596

AC:

31717

AN:

53242

Middle Eastern (MID)

AF:

0.643

AC:

3671

AN:

5710

European-Non Finnish (NFE)

AF:

0.614

AC:

677695

AN:

1104214

Other (OTH)

AF:

0.573

AC:

34422

AN:

60066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

14881

29763

44644

59526

74407

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17982

35964

53946

71928

89910

<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:

0.501

AC:

76013

AN:

151868

Hom.:

20795

Cov.:

AF XY:

0.498

AC XY:

36943

AN XY:

74210

show subpopulations

African (AFR)

AF:

0.287

AC:

11900

AN:

41396

American (AMR)

AF:

0.445

AC:

6792

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.684

AC:

2373

AN:

3468

East Asian (EAS)

AF:

0.356

AC:

1836

AN:

5156

South Asian (SAS)

AF:

0.567

AC:

2725

AN:

4810

European-Finnish (FIN)

AF:

0.600

AC:

6316

AN:

10518

Middle Eastern (MID)

AF:

0.599

AC:

176

AN:

294

European-Non Finnish (NFE)

AF:

0.620

AC:

42160

AN:

67954

Other (OTH)

AF:

0.529

AC:

1118

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1753

3507

5260

7014

8767

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

670

1340

2010

2680

3350

<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:

0.502

Hom.:

3488

Bravo

AF:

0.478

Asia WGS

AF:

0.441

AC:

1531

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

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

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Neurofibromatosis, type 1

Benign:2

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

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

-0.76

CADD

Benign

(source)

DANN

Benign

0.55

PhyloP100

1.2

BranchPoint Hunter

2.0

Mutation Taster

=96/4

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