dbSNP rs7215555: NF1:c.3974+1564G>A (chr17-31237585-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001042492.3(NF1):c.3974+1564G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.763 in 151,400 control chromosomes in the GnomAD database, including 44,960 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.76 ( 44960 hom., cov: 29)

Consequence

NF1
NM_001042492.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.617

Publications

11 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.01).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.927 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3 link	c.3974+1564G>A		intron_variant	Intron 29 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4 link	c.3974+1564G>A		intron_variant	Intron 29 of 56		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 link	c.3974+1564G>A		intron_variant	Intron 29 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes

AF:

0.762

AC:

115351

AN:

151284

Hom.:

44883

Cov.:

show subpopulations

Gnomad AFR

AF:

0.934

Gnomad AMI

AF:

0.719

Gnomad AMR

AF:

0.787

Gnomad ASJ

AF:

0.647

Gnomad EAS

AF:

0.627

Gnomad SAS

AF:

0.576

Gnomad FIN

AF:

0.734

Gnomad MID

AF:

0.680

Gnomad NFE

AF:

0.687

Gnomad OTH

AF:

0.763

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.763

AC:

115495

AN:

151400

Hom.:

44960

Cov.:

AF XY:

0.762

AC XY:

56296

AN XY:

73916

show subpopulations

African (AFR)

AF:

0.934

AC:

38574

AN:

41278

American (AMR)

AF:

0.788

AC:

11987

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.647

AC:

2235

AN:

3456

East Asian (EAS)

AF:

0.629

AC:

3229

AN:

5136

South Asian (SAS)

AF:

0.578

AC:

2768

AN:

4788

European-Finnish (FIN)

AF:

0.734

AC:

7599

AN:

10356

Middle Eastern (MID)

AF:

0.673

AC:

198

AN:

294

European-Non Finnish (NFE)

AF:

0.687

AC:

46641

AN:

67858

Other (OTH)

AF:

0.765

AC:

1611

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1277

2554

3830

5107

6384

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

838

1676

2514

3352

4190

<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:

0.697

Hom.:

20017

Bravo

AF:

0.774

Asia WGS

AF:

0.644

AC:

2244

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.40

(source)

DANN

Benign

0.15

PhyloP100

-0.62

Mutation Taster

=94/6

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over