rs1057518792

Variant names:

• chr17-31229024-G-A
• rs1057518792
• NM_001042492.3:c.2410-1G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-31229024-G-A
• chr17-31229024-G-C
• chr17-31229024-G-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001042492.3(NF1):​c.2410-1G>A variant causes a splice acceptor, intron change. 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.89
• Publications: 1 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.05176056 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.9, offset of 1, new splice context is: acaaaaattttgtgtttaAGctg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-31229024-G-A is Pathogenic according to our data. Variant chr17-31229024-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 373947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.2410-1G>A		splice_acceptor_variant, intron_variant	Intron 20 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.2410-1G>A		splice_acceptor_variant, intron_variant	Intron 20 of 56		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.2410-1G>A		splice_acceptor_variant, intron_variant	Intron 20 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:2

Oct 25, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 23913538). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 373947). This variant is also known as IVS15–1G–A. Disruption of this splice site has been observed in individual(s) with neurofibromatosis type I (PMID: 10543400, 33443663). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 20 of the NF1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. -

Mar 15, 2022

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cafe au lait spots, multiple Pathogenic:1

Jun 06, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Mar 10, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2410-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 21 of the NF1 gene. This alteration (referred to as IVS15-1G>A) was reported in an individual with a clinical diagnosis of neurofibromatosis type 1, and RT-PCR analysis demonstrated that this alteration disrupts splicing and results in a truncated transcript (Osborn MJ et al. Hum. Genet., 1999 Oct;105:327-32). 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	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		5.9
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.95		Position offset: 2
DS_AL_spliceai		0.98		Position offset: 1

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

Other links and lift over

dbSNP: rs1057518792; hg19: chr17-29556042;