rs1555612294

chr17-31214585-TGTAA-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1_Moderate PM2 PP3 PP5_Very_Strong

The NM_001042492.3(NF1):c.1527+4_1527+7del variant causes a splice donor, splice donor 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. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NF1 NM_001042492.3 splice_donor, splice_donor_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• 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 13 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.007863849 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• 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/exons	MANE	UniProt
NF1	NM_001042492.3	c.1527+4_1527+7del		splice_donor_variant, splice_donor_region_variant, intron_variant		ENST00000358273.9
NF1	NM_000267.3	c.1527+4_1527+7del		splice_donor_variant, splice_donor_region_variant, intron_variant
NF1	NM_001128147.3	c.1527+4_1527+7del		splice_donor_variant, splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.1527+4_1527+7del		splice_donor_variant, splice_donor_region_variant, intron_variant		1	NM_001042492.3	P1

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 08, 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. 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; Invitae). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 07, 2023

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 21, 2021

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;