dbSNP rs2040792: NF1:c.4836-24289C>A (chr17-31301531-C-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.4836-24289C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.487 in 151,874 control chromosomes in the GnomAD database, including 20,169 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 0.49 ( 20169 hom., cov: 31)

Consequence

NF1
NM_001042492.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.00100

Publications

16 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=-0.61).

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.4836-24289C>A		intron_variant	Intron 36 of 57	ENST00000358273.9	NP_001035957.1	P21359-1
NF1	NM_000267.4 link	c.4773-24289C>A		intron_variant	Intron 35 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.4836-24289C>A		intron_variant	Intron 36 of 57	1	NM_001042492.3	ENSP00000351015.4		P21359-1

Frequencies

GnomAD3 genomes

AF:

0.487

AC:

73950

AN:

151754

Hom.:

20164

Cov.:

show subpopulations

Gnomad AFR

AF:

0.243

Gnomad AMI

AF:

0.678

Gnomad AMR

AF:

0.440

Gnomad ASJ

AF:

0.682

Gnomad EAS

AF:

0.347

Gnomad SAS

AF:

0.568

Gnomad FIN

AF:

0.602

Gnomad MID

AF:

0.583

Gnomad NFE

AF:

0.620

Gnomad OTH

AF:

0.520

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

GnomAD4 genome

AF:

0.487

AC:

73977

AN:

151874

Hom.:

20169

Cov.:

AF XY:

0.485

AC XY:

35998

AN XY:

74202

show subpopulations

African (AFR)

AF:

0.244

AC:

10107

AN:

41446

American (AMR)

AF:

0.440

AC:

6699

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.682

AC:

2365

AN:

3468

East Asian (EAS)

AF:

0.347

AC:

1791

AN:

5168

South Asian (SAS)

AF:

0.566

AC:

2731

AN:

4824

European-Finnish (FIN)

AF:

0.602

AC:

6326

AN:

10512

Middle Eastern (MID)

AF:

0.586

AC:

171

AN:

292

European-Non Finnish (NFE)

AF:

0.620

AC:

42081

AN:

67910

Other (OTH)

AF:

0.517

AC:

1092

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1738

3475

5213

6950

8688

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

654

1308

1962

2616

3270

<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:

0.520

Hom.:

4239

Bravo

AF:

0.463

Asia WGS

AF:

0.433

AC:

1505

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

1.8

(source)

DANN

Benign

0.69

PhyloP100

0.0010

Mutation Taster

=97/3

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