17-31159097-A-G

Variant names:

• chr17-31159097-A-G
• rs781459468
• NM_001042492.3:c.288+4A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001042492.3(NF1):​c.288+4A>G variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on 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: 0.7967
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 4.70

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-31159097-A-G is Pathogenic according to our data. Variant chr17-31159097-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 404451.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1, Pathogenic=3}. Variant chr17-31159097-A-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.288+4A>G		splice_region_variant, intron_variant	Intron 3 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.288+4A>G		splice_region_variant, intron_variant	Intron 3 of 56		NP_000258.1
NF1	NM_001128147.3	c.288+4A>G		splice_region_variant, intron_variant	Intron 3 of 14		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.288+4A>G		splice_region_variant, intron_variant	Intron 3 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:3

Aug 17, 2022

Medical Genetics, University of Parma

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 3 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 individuals with clinical features of NF1-related conditions (PMID: 31370276; internal data). ClinVar contains an entry for this variant (Variation ID: 404451). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Nov 11, 2024

NHS Central & South Genomic Laboratory Hub

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:3

Feb 17, 2021

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Assessment of experimental evidence suggests this variant will result in the removal of a section of the protein due to abnormal RNA splicing (PMID: 31370276). This variant has been identified in at least one individual with clinical features associated with this gene. Several other splice variants at this junction are reported to be pathogenic or likely pathogenic. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). -

Oct 19, 2020

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies report this variant results in an in-frame deletion of 28 amino acids in a non-repeat region (Giugliano 2019); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 31370276) -

Apr 14, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NF1 c.288+4A>G variant disrupts a canonical splice-donor site and interferes with normal NF1 mRNA splicing. This variant has been reported in the published literature in individuals with neurofibromatosis 1 (NF1) (PMID: 31370276 (2019) and Quest internal data). Assessment of experimental evidence suggests this variant will result in the removal of a section of the protein due to abnormal RNA splicing (PMID: 31370276 (2019), 17311297 (2007)). This variant has not been reported in large, multiethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

Neurofibromatosis-Noonan syndrome Uncertain:1

Jun 25, 2024

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence variant is a single nucleotide substitution (A>G) 4 bases downstream of the donor splice site of exon 3 of 58 in the NF1 gene. This is a previously reported variant (ClinVar 404451) that has been observed in an individual with phenotypes consistent with neurofibromatosis type 1 (PMID: 31370276). This variant is absent from the gnomAD v4.1.0 population database (0/1586428 alleles). In silico splice tools predict that this A to G base change will disrupt splicing, and the nucleotide at this position is moderately conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have not been published, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: PM2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	19
DANN	Benign	0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.80
dbscSNV1_RF	Benign	0.51
SpliceAI score (max)		0.70		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.70		Position offset: -4

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

Publications

LitVar

Other links and lift over

dbSNP: rs781459468; hg19: chr17-29486115;