17-31230383-G-T

Variant names:

• chr17-31230383-G-T
• rs267606599
• NM_001042492.3:c.3113+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.3113+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: 9.56

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 0.014436619 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 17-31230383-G-T is Pathogenic according to our data. Variant chr17-31230383-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 216062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31230383-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.3113+1G>T		splice_donor_variant, intron_variant	Intron 23 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.3113+1G>T		splice_donor_variant, intron_variant	Intron 23 of 56		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.3113+1G>T		splice_donor_variant, intron_variant	Intron 23 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:4

Mar 15, 2022

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 29, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NF1 c.3113+1G>T variant is classified as Pathogenic (PVS1_Moderate, PS4_Moderate, PM2) -

Jul 30, 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 23 of the NF1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered 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: 10607834, 12807981, 16944272, 18546366). This variant is also known as IVS18+1G>T. ClinVar contains an entry for this variant (Variation ID: 216062). Studies have shown that disruption of this splice site results in skipping of exon 23, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 7633431, 10607834, 12807981). For these reasons, this variant has been classified as Pathogenic. -

Juvenile myelomonocytic leukemia Pathogenic:1

Feb 25, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Oct 22, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3113+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 23 of the NF1 gene. This mutation has been detected in multiple individuals who fulfilled diagnostic criteria for neurofibromatosis type 1 or with features of NF1 (Griffiths S et al. Fam Cancer, 2007;6:21-34; Sabbagh A et al. Hum Mutat, 2013 Nov;34:1510-8; Kang E et al. J Hum Genet, 2020 Jan;65:79-89). RNA studies have demonstrated that the alteration results in skipping of exon 23, leading to an in-frame deletion in a region critical to protein function (Ars E et al. J Med Genet, 2003 Jun;40:e82). Another alteration impacting the same donor site (c.3113+1G>A) has been detected in NF1 patients and has been shown to result in skipping of exon 23 by RNA studies (Upadhyaya M et al. Hum. Mutat., 2008 Aug;29:E103-11; Thomas L et al. Eur. J. Hum. Genet., 2012 Apr;20:411-9; Emmerich D et al. Eur. J. Hum. Genet., 2015 Jun;23:870-3; Hutter S et al. Hum. Genet., 2016 May;135:469-75; Purandare SM et al. Hum. Mol. Genet., 1995 Apr;4:767-8; Ars E et al. J. Med. Genet., 2003 Jun;40:e82; Pros E et al. Hum. Mutat., 2008 Sep;29:E173-93; Ambry internal data). The c.3113+1G>T variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. 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	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.3

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_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: rs267606599; hg19: chr17-29557401; COSMIC: COSV62198325; COSMIC: COSV62198325;