rs1131691067

chr17-31203089-A-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 criteria provided, multiple submitters, no conflicts P:10
• 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/exons	MANE	UniProt
NF1	NM_001042492.3	c.1260+1604A>G		intron_variant		ENST00000358273.9
NF1	NM_000267.3	c.1260+1604A>G		intron_variant
NF1	NM_001128147.3	c.1260+1604A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.1260+1604A>G		intron_variant		1	NM_001042492.3	P1

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

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2023	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 disrupted 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; Invitae). 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 introduces a premature termination codon (PMID: 11115850, 23913538; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Medical Genetics, University of Parma	Dec 20, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Dec 07, 2021	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 12, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	NF1: PVS1, PM2, PS4:Moderate, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2022	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) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 05, 2015	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. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jan 12, 2021	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2022

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;