rs1131691089

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_ModeratePP5

The NM_001042492.3(NF1):c.3198-2A>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 16)

Exomes 𝑓: 0.0000046 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NF1
NM_001042492.3 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 8.85

Publications

1 publications found

Variant links:

COSMIC-nc: COSV62219542

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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
neurofibromatosis-Noonan syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
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: Unknown Classification: NO_KNOWN Submitted by: ClinGen

NF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.013732394 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4, offset of 2, new splice context is: tttttttttttttttccgAGatt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PP5

Variant 17-31232071-A-C is Pathogenic according to our data. Variant chr17-31232071-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2736538.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042492.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	NM_001042492.3	MANE Select	c.3198-2A>C		splice_acceptor intron	N/A	NP_001035957.1	P21359-1
	NF1	NM_000267.4		c.3198-2A>C		splice_acceptor intron	N/A	NP_000258.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NF1	ENST00000358273.9	TSL:1 MANE Select	c.3198-2A>C	splice_acceptor intron	N/A	ENSP00000351015.4	P21359-1
NF1	ENST00000356175.7	TSL:1	c.3198-2A>C	splice_acceptor intron	N/A	ENSP00000348498.3	P21359-2
NF1	ENST00000579081.6	TSL:1	n.3198-2A>C	splice_acceptor intron	N/A	ENSP00000462408.2	J3KSB5

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

71202

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000464

AC:

AN:

431086

Hom.:

Cov.:

AF XY:

0.00000459

AC XY:

AN XY:

217810

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

8786

American (AMR)

AF:

0.00

AC:

AN:

9422

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10146

East Asian (EAS)

AF:

0.00

AC:

AN:

15954

South Asian (SAS)

AF:

0.0000557

AC:

AN:

17942

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25778

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1508

European-Non Finnish (NFE)

AF:

0.00000309

AC:

AN:

323104

Other (OTH)

AF:

0.00

AC:

AN:

18446

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

71202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32870

African (AFR)

AF:

0.00

AC:

AN:

14364

American (AMR)

AF:

0.00

AC:

AN:

5570

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2254

East Asian (EAS)

AF:

0.00

AC:

AN:

2520

South Asian (SAS)

AF:

0.00

AC:

AN:

2462

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3002

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

39538

Other (OTH)

AF:

0.00

AC:

AN:

968

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neurofibromatosis, type 1 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

1.0

PhyloP100

8.8

GERP RS

5.3

Mutation Taster

=1/99

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.97

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.66

Position offset: 4

DS_AL_spliceai

0.97

Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over