rs1135402799

Variant names:

• chr17-31182666-G-A
• rs1135402799
• NM_001042492.3:c.888+1G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-31182666-G-A
• chr17-31182666-G-C
• chr17-31182666-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001042492.3(NF1):​c.888+1G>A variant causes a splice donor, intron 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.92

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-31182666-G-A is Pathogenic according to our data. Variant chr17-31182666-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 547573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31182666-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.888+1G>A		splice_donor_variant, intron_variant	Intron 8 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.888+1G>A		splice_donor_variant, intron_variant	Intron 8 of 56		NP_000258.1
NF1	NM_001128147.3	c.888+1G>A		splice_donor_variant, intron_variant	Intron 8 of 14		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.888+1G>A		splice_donor_variant, intron_variant	Intron 8 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:3

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor 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 the gain of 20 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with neurofibromatosis type1 (PMID: 10712197, 28961165, 30530636; internal data). ClinVar contains an entry for this variant (Variation ID: 547573). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in intron 8 (PMID: 18546366; internal data). For these reasons, this variant has been classified as Pathogenic. -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 15, 2022

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Feb 09, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant demonstrated to result in abnormal gene splicing in a gene for which loss-of-function is a known mechanism of disease (PMID: 16741618, 18546366, 23913538, 30530636); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30530636, 16741618, 23913538, 10712197, 18546366, 31201679) -

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

Mar 16, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.888+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 8 of the NF1 gene. The mutation has been detected in multiple unrelated individuals diagnosed with or suspected of having neurofibromatosis type 1 (NF1) (Fahsold R et al. Am. J. Hum. Genet., 2000 Mar;66:790-818; Ars E et al. J. Med. Genet., 2003 Jun;40:e82; Pros E et al. Hum. Mutat., 2008 Sep;29:E173-93; Frayling IM et al. J. Med. Genet., 2019 04;56:209-219). This mutation was also reported to result in either skipping of exon 8 or activation of a cryptic donor site in intron 8 (Ars E et al. J. Med. Genet., 2003 Jun;40:e82; Pros E et al. Hum. Mutat., 2008 Sep;29:E173-93; Frayling IM et al. J. Med. Genet., 2019 04;56:209-219; Ambry internal data). Furthermore, other variants at the same donor site (c.888+1G>C and c.888+2T>G) have been identified in individuals diagnosed with or suspected of having NF1 (Pasmant E et al. Mol. Med. 2011 Sep;17:79-87; Bonatti F et al. Int J Mol Sci, 2017 Sep;18:). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	31
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1135402799; hg19: chr17-29509684;