dbSNP rs267606599: NF1:c.3113+1G>A (chr17-31230383-G-A) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_001042492.3(NF1):c.3113+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,084 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NF1
NM_001042492.3 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 9.56

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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-A is Pathogenic according to our data. Variant chr17-31230383-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31230383-G-A is described in Lovd as [Pathogenic]. Variant chr17-31230383-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3 link	c.3113+1G>A		splice_donor_variant, intron_variant	Intron 23 of 57	ENST00000358273.9	NP_001035957.1	P21359-1
NF1	NM_000267.3 link	c.3113+1G>A		splice_donor_variant, intron_variant	Intron 23 of 56		NP_000258.1	P21359-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 link	c.3113+1G>A		splice_donor_variant, intron_variant	Intron 23 of 57	1	NM_001042492.3	ENSP00000351015.4		P21359-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250808

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135668

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461084

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726834

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000468

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurofibromatosis, type 1

Pathogenic:10

Jan 28, 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 23 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 present in population databases (rs267606599, gnomAD 0.003%). Disruption of this splice site has been observed in individuals with neurofibromatosis, type 1 (PMID: 16944272, 18484666, 25293717, 26962827, 26969325). ClinVar contains an entry for this variant (Variation ID: 345). Studies have shown that disruption of this splice site results in skipping of exon 23, but is expected to preserve the integrity of the reading-frame (PMID: 7633431). For these reasons, this variant has been classified as Pathogenic. -

Oct 26, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

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

- -

Apr 02, 2020

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS3,PS4. -

Sep 25, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2023

Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is reported in the ClinVar database as pathogenic by 13 submitters (Accession ID: VCV000000345.39). This canonical splice-site variant is likely to result in aberrant splicing leading to either formation of a truncated protein product or the transcript to undergo nonsense-mediated mRNA decay. -

Apr 09, 2025

NHS Central & South Genomic Laboratory Hub

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 17, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS3 -

Apr 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:2

Nov 16, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant demonstrated to result in abnormal splicing leading to an in-frame deletion of a critical region (Purandare 1995); A different nucleotide change at this same canonical splice site (c.3113+1G>T) has been reported as pathogenic in ClinVar and at GeneDx (ClinVar SCV# SCV000253824.3; Landrum 2016); Also known as IVS18+1G>A; This variant is associated with the following publications: (PMID: 10712197, 25293717, 7633431, 16944272, 23913538, 26969325, 26962827, 18484666, 31370276, 31776437, 31533797) -

Nov 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NF1 c.3113+1G>A variant (rs267606599), also known as IVS18+1G>A in legacy nomenclature, is reported in the literature in several individuals affected with neurofibromatosis type 1 (Griffiths 2007, Kang 2020, Pros 2020). This variant is also reported in ClinVar (Variation ID: 345). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant disrupts the canonical splice donor site of intron 23, and functional analyses of the variant protein show this variant leads to skipping of exon 23 (Upadhyaya 2008, Purandare 1995). Based on available information, this variant is considered to be pathogenic. References: Griffiths S et al. Molecular diagnosis of neurofibromatosis type 1: 2 years experience. Fam Cancer. 2007;6(1):21-34. PMID: 16944272. Kang E et al. Phenotype categorization of neurofibromatosis type I and correlation to NF1 mutation types. J Hum Genet. 2020 Jan;65(2):79-89. PMID: 31776437. 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. PMID: 18546366. Purandare SM et al. Characterisation of a novel splice donor mutation affecting position +1 in intron 18 of the NF-1 gene. Hum Mol Genet. 1995 Apr;4(4):767-8. PMID: 7633431. Upadhyaya M et al. Germline and somatic NF1 gene mutations in plexiform neurofibromas. Hum Mutat. 2008 Aug;29(8):E103-11. PMID: 18484666. -

Neurofibromatosis, type 1;C4024216:Tibial pseudarthrosis

Pathogenic:1

Nov 10, 2018

The Laboratory of Genetics and Metabolism, Hunan Children’s Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

NF1-related disorder

Pathogenic:1

Aug 30, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NF1 c.3113+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in multiple unrelated individuals with neurofibromatosis type 1 (see for example - Upadhyaya et al. 2008. PubMed ID: 18484666; Table S1 - Pros et al. 2008. PubMed ID: 18546366). Splicing studies found this variant results in skipping of exon 18 which is predicted to result in an inframe deletion (Table S1 - Pros et al. 2008. PubMed ID: 18546366). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. Variants that disrupt the consensus splice donor site in NF1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Pathogenic:1

Sep 10, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3113+1G>A intronic pathogenic mutation results from a G to A 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 (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). In addition to the clinical data presented in the literature, 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 (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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Mar 18, 2022

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over