17-31227607-G-T

Variant names:

• chr17-31227607-G-T
• rs1555614022
• NM_001042492.3:c.2409+1G>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001042492.3(NF1):​c.2409+1G>T 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:6
• Conservation: PhyloP100: 9.36

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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.009859155 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-31227607-G-T is Pathogenic according to our data. Variant chr17-31227607-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 449423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31227607-G-T is described in Lovd as [Pathogenic]. Variant chr17-31227607-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.2409+1G>T		splice_donor_variant, intron_variant	Intron 20 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.2409+1G>T		splice_donor_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.2409+1G>T		splice_donor_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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:2

Sep 27, 2024

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 20 of the NF1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features of neurofibromatosis type 1 (PMID: 16835897, 18546366; internal data). ClinVar contains an entry for this variant (Variation ID: 449423). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Mar 15, 2022

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Mar 30, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NF1 c.2409+1G>T variant disrupts a canonical splice-donor site and interferes with normal NF1 mRNA splicing. The variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported to cause exon skipping, and identified in individuals affected with NF1 (PMIDs: 16835897 (2006), 18546366 (2008)). Based on the available information, this variant is classified as pathogenic. -

Aug 31, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant confirmed by patient RNA analysis (Pros et al, 2008) to result in the predicted in-frame deletion of exon 20 (also denoted exon 15 by alternate exon numbering) which contains a portion of the critical GTPase activating protein domain (Luo et al., 2014); Not observed at significant frequency in large population cohorts (Lek et al., 2016); Identified in patients with features of neurofibromatosis type 1 referred for genetic testing at GeneDx and in published literature (Lee et al, 2006; Pros et al, 2008); This variant is associated with the following publications: (PMID: 16835897, 18546366, 25525159) -

See cases Pathogenic:1

Aug 01, 2022

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PVS1,PS1,PP5 -

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

Jan 16, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2409+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 20 of the NF1 gene. This variant has been detected in multiple individuals with a clinical diagnosis or suspicion of neurofibromatosis type 1 (NF1) (Lee MJ et al. Hum Mutat, 2006 Aug;27:832; Pros E et al. Hum Mutat, 2008 Sep;29:E173-93; Ambry internal data). Other alterations impacting the same donor site (c.2409+1G>A, c.2409+1G>C, and c.2409+2T>G) have also been identified in individuals with a clinical diagnosis or suspicion of NF1 (Lee MJ et al. Hum Mutat, 2006 Aug;27:832; Maynard J et al. Hum Genet, 1997 May;99:674-6; Bausch B et al. J Clin Endocrinol Metab, 2007 Jul;92:2784-92). In addition, RNA studies have demonstrated that c.2409+1G>T results in skipping of exon 20 (Pros E et al. Hum Mutat, 2008 Sep;29:E173-93; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		4.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.33		Position offset: -2
DS_DL_spliceai		1.0		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: rs1555614022; hg19: chr17-29554625;