rs878853922

chr17-31200420-A-Gchr17-31200420-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1_Moderate PM2 PP3_Strong PP5

The NM_001042492.3(NF1):c.889-2A>G variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 8.58

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.010152582 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-31200420-A-G is Pathogenic according to our data. Variant chr17-31200420-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 237610.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=6, Uncertain_significance=1}. Variant chr17-31200420-A-G is described in Lovd as [Pathogenic]. Variant chr17-31200420-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.889-2A>G		splice_acceptor_variant		ENST00000358273.9
NF1	NM_000267.3	c.889-2A>G		splice_acceptor_variant
NF1	NM_001128147.3	c.889-2A>G		splice_acceptor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.889-2A>G		splice_acceptor_variant		1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2022	Intronic variant predicted to result in an in-frame deletion of exon 9 and has been confirmed via RT-PCR (Klose 1999, Pros 2008, Xu 2014); Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); Not observed in large population cohorts (gnomAD); Also known as IVS6-2A>G; This variant is associated with the following publications: (PMID: 25525159, 24789688, 10076878, 30530636, 30308447, 31730495, 22155606, 14722917, 10712197, 18546366, 21280148, 26969325) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 09, 2018	The variant disrupts a canonical splice site, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and not found in general population data. -

Neurofibromatosis, type 1 Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 10, 2024	This sequence change affects an acceptor splice site in intron 8 of the NF1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10076878, 30308447, 31730495). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 237610). Studies have shown that disruption of this splice site results in skipping of exon 9, but is expected to preserve the integrity of the reading-frame (PMID: 10076878, 18546366). For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 17, 2019	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 04, 2018

The NF1 c.889-2A>G variant (rs878853922) is reported in the literature in multiple individuals affected with neurofibromatosis type 1 (Klose 1999, Messiaen 2011, Xu 2014). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 237610), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant disrupts the canonical splice acceptor site of intron 8, which is likely to disrupt gene function, and in vitro functional analyses demonstrate skipping of exon 7 (Klose 1999, Pros 2008, Xu 2014). Based on available information, the c.889-2A>G variant is considered to be pathogenic. References: Klose A et al. Two independent mutations in a family with neurofibromatosis type 1 (NF1). Am J Med Genet. 1999 Mar 5;83(1):6-12. Messiaen L et al. Mosaic type-1 NF1 microdeletions as a cause of both generalized and segmental neurofibromatosis type-1 (NF1). Hum Mutat. 2011 Feb;32(2):213-9. Pros E et al. Nature and mRNA effect of 282 different NF1 point mutations: focus on splicing alterations. Hum Mutat. 2008 Sep;29(9):E173-93. Xu W et al. Fifty-four novel mutations in the NF1 gene and integrated analyses of the mutations that modulate splicing. Int J Mol Med. 2014 Jul;34(1):53-60. -

Juvenile myelomonocytic leukemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 02, 2022

- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2018

The c.889-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 9 in the NF1 gene. This mutation has been identified in multiple individuals and families with neurofibromatosis type 1 (NF1), and has been shown via RT-PCR studies to cause aberrant splicing leading to the skipping of exon 7 (coding exon 9) (Klose A et al. Am. J. Med. Genet., 1999 Mar;83:6-12; Pros E et al. Hum. Mutat., 2008 Sep;29:E173-93; Messiaen L et al. Hum. Mutat., 2011 Feb;32:213-9; Xu W et al. Int. J. Mol. Med., 2014 Jul;34:53-60). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	30
Dann	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		5.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.87		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs878853922; hg19: chr17-29527438;