17-31214590-G-C

Position:

• chr17-31214590-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_001042492.3(NF1):​c.1527+5G>C variant causes a splice region, intron change involving the alteration of a conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 splice_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• Conservation: PhyloP100: 9.35

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 4: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, phyloP100way_vertebrate [when BayesDel_noAF, Cadd was below the threshold]
• PP5: Variant 17-31214590-G-C is Pathogenic according to our data. Variant chr17-31214590-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 457537.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, other=1, Likely_pathogenic=2}. Variant chr17-31214590-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.1527+5G>C		splice_region_variant, intron_variant		ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.1527+5G>C		splice_region_variant, intron_variant			NP_000258.1
NF1	NM_001128147.3	c.1527+5G>C		splice_region_variant, intron_variant			NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.1527+5G>C		splice_region_variant, intron_variant		1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genetics Bochum, Ruhr University Bochum	Aug 01, 2022	ACMG criteria used to clasify this variant: PM1, PM2, PP3, PP1, PS4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2023	This sequence change falls in intron 13 of the NF1 gene. It does not directly change the encoded amino acid sequence of the NF1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 457537). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.1527+5 nucleotide in the NF1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 17311297; Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 03, 2023

The c.1527+5G>C intronic variant results from a G to C substitution 5 nucleotides after coding exon 13 in the NF1 gene. This variant has been detected in individuals with features consistent with neurofibromatosis type 1 (NF1) (external communication; Ambry internal data). In addition, RNA studies have demonstrated that this alteration results in abnormal splicing (external communication). Another alteration impacting the same donor site (c.1527+5G>A) has been reported in association with NF1 (Melloni G et al. Cancers (Basel). 2019 Nov;11(12)). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Neoplasm Other:1

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.66		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.66		Position offset: -5

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060500352; hg19: chr17-29541608;