rs1555612294

Variant names:

• chr17-31214585-TGTAA-T
• rs1555612294
• NM_001042492.3:c.1527+4_1527+7delAGTA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The ENST00000358273.9(NF1):​c.1527+1_1527+4delGTAA variant causes a splice donor, splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,490 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NF1 ENST00000358273.9 splice_donor, splice_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• 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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.01584507 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-31214585-TGTAA-T is Pathogenic according to our data. Variant chr17-31214585-TGTAA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 457536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31214585-TGTAA-T is described in Lovd as [Pathogenic]. Variant chr17-31214585-TGTAA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.1527+4_1527+7delAGTA		splice_region_variant, intron_variant	Intron 13 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.1527+4_1527+7delAGTA		splice_region_variant, intron_variant	Intron 13 of 56		NP_000258.1
NF1	NM_001128147.3	c.1527+4_1527+7delAGTA		splice_region_variant, intron_variant	Intron 13 of 14		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.1527+1_1527+4delGTAA		splice_donor_variant, splice_region_variant, intron_variant	Intron 13 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460490 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 726606

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:3

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened 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: 11258625, 12807981; internal data). This variant is also known as IVS10b+4delAGTA or IVS10b+2delTAAG. ClinVar contains an entry for this variant (Variation ID: 457536). 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 skipping of exon 13, but is expected to preserve the integrity of the reading-frame (PMID: 11258625). For these reasons, this variant has been classified as Pathogenic. -

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 15, 2022

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Aug 28, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NF1 c.1527+4_1527+7del variant has been reported in the published literature in individuals with neurofibromatosis 1, including one individual where the variant was reported to occur de novo (PMID: 38405018 (2024), 27322474 (2016), 18546366 (2008), 12807981 (2003)). Functional studies demonstrated that this variant disrupted mRNA splicing, however exon skipping was in-frame (PMID: 27322474 (2016), 12807981 (2003)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper NF1 mRNA splicing. Based on the available information, this variant is classified as likely pathogenic. -

Apr 07, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Non-canonical splice site variant demonstrated to result in aberrant splicing leading to loss of the adjacent exon (Messiaen et al., 1999; Pros et al., 2008; Evans et al., 2016); Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Also known as IVS10b+2delTAAG; This variant is associated with the following publications: (PMID: 11258625, 18546366, 27322474, 17576681, 9536098, 12807981, Bakir2023) -

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

Jul 21, 2021

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1527+4_1527+7delAGTA intronic variant is located 4 nucleotides after coding exon 13 of the NF1 gene. This variant results from a deletion of 4 nucleotides at positions c.1527+4 to c.1527+7. This alteration has been detected in multiple individuals meeting diagnostic criteria or suspicious for neurofibromatosis type 1 (NF1) (Messiaen LM et al. Genet Med. 1999 Sep-Oct;1(6):248-53; Ars E et al. J Med Genet. 2003 Jun;40(6):e82; Evans DG et al. EBioMedicine. 2016 May;7:212-20). RNA analysis demonstrated that this alteration causes in-frame skipping of coding exon 13 (Messiaen LM et al. Genet Med. 1999 Sep-Oct;1(6):248-53; Ars E et al. J Med Genet. 2003 Jun;40(6):e82). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		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: rs1555612294; hg19: chr17-29541603;