rs1131691080

Variant names:

• chr17-31223567-G-A
• rs1131691080
• NM_001042492.3:c.1845G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-31223567-G-A
• chr17-31223567-G-C
• chr17-31223567-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001042492.3(NF1):​c.1845G>A​(p.Lys615Lys) variant causes a splice region, synonymous change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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_region, synonymous
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.94

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-31223567-G-A is Pathogenic according to our data. Variant chr17-31223567-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 578879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31223567-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.1845G>A	p.Lys615Lys	splice_region_variant, synonymous_variant	Exon 16 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.1845G>A	p.Lys615Lys	splice_region_variant, synonymous_variant	Exon 16 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.1845G>A	p.Lys615Lys	splice_region_variant, synonymous_variant	Exon 16 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:3

Mar 15, 2022

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2023

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 615 of the NF1 mRNA. It is a 'silent' change, meaning that it does not 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 clinical features of neurofibromatosis, type 1 (PMID: 26740943; internal data). ClinVar contains an entry for this variant (Variation ID: 578879). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in disrupted mRNA splicing, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 26740943). This variant disrupts the p.Lys615 nucleotide in the NF1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 18546366, 23322702, 25541118, 28422438, 29673180). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Jun 17, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Nov 01, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1845G>A pathogenic mutation (also known as p.K615K), located in coding exon 16 of the NF1 gene, results from a G to A substitution at nucleotide position 1845. This nucleotide substitution does not change the lysine at codon 615. However, this change occurs in the last base pair of coding exon 16, which makes it likely to have some effect on normal mRNA splicing. This mutation was detected in an individual with a clinical diagnosis or suspicion of neurofibromatosis type 1 (NF1) (Bianchessi D et al. Mol Genet Genomic Med, 2015 Nov;3:513-25). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this mutation results in abnormal splicing (Bianchessi D et al. Mol Genet Genomic Med, 2015 Nov;3:513-25; Ambry internal data). Another alteration impacting the same donor site (c.1845G>T) has been detected in individuals with NF1 and shown to have a similar impact on splicing (Pros E et al. Hum Mutat, 2008 Sep;29:E173-93; Sabbagh A et al. Hum Mutat, 2013 Nov;34:1510-8). c.1845G>A 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_noAF	Benign	-0.17
CADD	Benign	21
DANN	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.85		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1131691080; hg19: chr17-29550585;