rs1060500352

chr17-31214590-G-Achr17-31214590-G-Cchr17-31214590-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001042492.3(NF1):c.1527+5G>A variant causes a splice donor 5th base, 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. 2/2 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_donor_5th_base, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U: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 Likely_pathogenic. Variant got 7 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. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-31214590-G-A is Pathogenic according to our data. Variant chr17-31214590-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 404566.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2, Pathogenic=2}. Variant chr17-31214590-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.1527+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000358273.9
NF1	NM_000267.3	c.1527+5G>A		splice_donor_5th_base_variant, intron_variant
NF1	NM_001128147.3	c.1527+5G>A		splice_donor_5th_base_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.1527+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 26, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 05, 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 been observed in individual(s) with clinical features of neurofibromatosis type 1 (PMID: 17311297; Invitae). ClinVar contains an entry for this variant (Variation ID: 404566). 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. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 21, 2021

Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect, although in the absence of functional evidence the actual effect of this sequence change is unknown; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 31766501, 17311297) -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2022

The c.1527+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 13 in the NF1 gene. This nucleotide position is highly conserved in available vertebrate species. This variant was detected in multiple individuals with features of or clinical diagnosis of neurofibromatosis type 1 (Melloni G et al. Cancers (Basel), 2019 11;11:; personal communication with GeneDx, Invitae, and the Hospital for Sick Children). In silico splice site analysis predicts that this alteration may weaken the native splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	24
Dann	Uncertain	0.97
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	1.0
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.36		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;