rs1131691067

Variant names:

• chr17-31203089-A-G
• rs1131691067
• NM_001042492.3:c.1260+1604A>G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_001042492.3(NF1):​c.1260+1604A>G variant causes a intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 4.25

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-31203089-A-G is Pathogenic according to our data. Variant chr17-31203089-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 428941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31203089-A-G is described in Lovd as [Pathogenic]. Variant chr17-31203089-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.1260+1604A>G		intron_variant	Intron 11 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.1260+1604A>G		intron_variant	Intron 11 of 56		NP_000258.1
NF1	NM_001128147.3	c.1260+1604A>G		intron_variant	Intron 11 of 14		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.1260+1604A>G		intron_variant	Intron 11 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:6

Dec 20, 2019

Medical Genetics, University of Parma

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely 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

- -

Dec 07, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 11 of the NF1 gene. It does not directly change the encoded amino acid sequence of the NF1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with neurofibromatosis type 1 (PMID: 21354044, 23913538, 27999334; internal data). In at least one individual the variant was observed to be de novo. This variant is also known as IVS9+1604A>G. ClinVar contains an entry for this variant (Variation ID: 428941). Studies have shown that this variant results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 11115850, 23913538; internal data). For these reasons, this variant has been classified as Pathogenic. -

Feb 18, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NF1 c.1260+1604A>G is located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a cryptic 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Koczkowska_2023). The variant was absent in 31406 control chromosomes (gnomAD). c.1260+1604A>G has been reported in the literature in multiple individuals affected with Neurofibromatosis Type 1 (Koczkowska_2023). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 37186028). ClinVar contains an entry for this variant (Variation ID: 428941). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:5

Apr 25, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Non-canonical splice site variant demonstrated to result in aberrant splicing leading to protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Valero 2011, Sabbagh 2013, Evans 2016, Wang 2017, Assunto 2019, Giugliano 2019); No data available from ethnically-matched control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 30530636, 31730495, 30104415, 21354044, 31370276, 27999334, 27322474, 23913538, 32486389, 11115850, 28891274, 34782607, 34573290) -

Nov 12, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 19, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NF1 c.1260+1604A>G variant (rs1131691067) is reported in the literature in multiple individuals with NF1 (Assunto 2019, Giugliano 2019, Koster 2021, Valero 2011, Wang 2018). This variant is also reported in ClinVar (Variation ID: 428941). It is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This is an intronic variant and RNA analysis has demonstrated that this variant creates a cryptic splice site leading to a premature termination codon (Valero 2011). Based on available information, this variant is considered to be pathogenic. References: Assunto A et al. Isoform-specific NF1 mRNA levels correlate with disease severity in Neurofibromatosis type 1. Orphanet J Rare Dis. 2019 Nov 15;14(1):261. PMID: 31730495. Giugliano T et al. Clinical and Genetic Findings in Children with Neurofibromatosis Type 1, Legius Syndrome, and Other Related Neurocutaneous Disorders. Genes (Basel). 2019 Jul 31;10(8):580. PMID: 31370276. Koster R et al. Pathogenic neurofibromatosis type 1 (NF1) RNA splicing resolved by targeted RNAseq. NPJ Genom Med. 2021 Nov 15;6(1):95. PMID: 34782607. Valero MC et al. A highly sensitive genetic protocol to detect NF1 mutations. J Mol Diagn. 2011 Mar;13(2):113-22. PMID: 21354044. Wang X et al. Breast cancer risk and germline genomic profiling of women with neurofibromatosis type 1 who developed breast cancer. Genes Chromosomes Cancer. 2018 Jan;57(1):19-27. PMID: 28891274. -

Nov 09, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NF1 c.1260+1604A>G variant has been reported in the published literature in several individuals with neurofibromatosis 1 (NF1) (PMID: 23913538 (2013), 21354044 (2011), 27322474 (2016), 27999334 (2016), 28891274 (2018), 31370276 (2019), 31730495 (2019)). In addition, studies have shown that this variant causes an insertion of cryptic exon resulting in frameshift and a truncated protein product (PMID: 21354044 (2011), 23913538 (2013)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NF1: PVS1, PM2, PS4:Moderate, PP4 -

Hereditary cancer-predisposing syndrome Pathogenic:2

Jan 12, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Nov 05, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1260+1604A>G intronic pathogenic mutation results from an A to G substitution 1604 nucleotides after coding exon 11 in the NF1 gene.Thismutation has been reported in several individuals withneurofibromatosis type 1 (NF1), one of whom met the NIH clinical diagnostic criteria for NF1.In addition,in vitrostudies havedemonstrated that this alteration affectssplicing and causesan insertion of a crypticexonthat shifts the reading frame, ultimately causing a premature stopcodon(Valero MC et al. J MolDiagn. 2011;13(2):113-122;SabbaghA et al.HumMutat. 2013 Nov;34(11):1510-8). Based on the available evidence, c.1260+1604A>Gis classified as a pathogenic mutation. -

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

Nov 29, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1260+1604A>G intronic pathogenic mutation results from an A to G substitution 1604 nucleotides after coding exon 11 in the NF1 gene. This mutation has been reported in several individuals who met the NIH clinical diagnostic criteria for neurofibromatosis type 1 (NF1) (Wang X et al. Genes Chromosomes Cancer. 2018 Jan;57:19-27; Sabbagh A et al. Hum. Mutat. 2013 Nov;34:1510-8; Evans DG et al. EBioMedicine. 2016 May;7:212-20). In addition, RNA studies have demonstrated that this alteration creates a new acceptor site, leading to an insertion of a cryptic exon that introduces a premature termination codon (Valero MC et al. J Mol Diagn. 2011;13(2):113-122; Sabbagh A et al. Hum Mutat. 2013 Nov;34(11):1510-8; Ambry internal data). 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_noAF	Benign	-0.30
CADD	Benign	19
DANN	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.76		Position offset: 1
DS_DG_spliceai		0.75		Position offset: 42

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

Publications

LitVar

Other links and lift over

dbSNP: rs1131691067; hg19: chr17-29530107;