rs1555612294

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001042492.3(NF1):​c.1527+4_1527+7delAGTA variant causes a 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 NM_001042492.3 splice_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.35
• Publications: 1 publications found

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]

NF1 Gene-Disease associations (from GenCC):

• neurofibromatosis type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
• Moyamoya disease

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-31214585-TGTAA-T is Pathogenic according to our data. Variant chr17-31214585-TGTAA-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 457536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042492.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	NM_001042492.3	MANE Select	c.1527+4_1527+7delAGTA		splice_region intron	N/A	NP_001035957.1
	NF1	NM_000267.4		c.1527+4_1527+7delAGTA		splice_region intron	N/A	NP_000258.1
	NF1	NM_001128147.3		c.1527+4_1527+7delAGTA		splice_region intron	N/A	NP_001121619.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.1527+1_1527+4delGTAA		splice_donor splice_region intron	N/A	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.1527+1_1527+4delGTAA		splice_donor splice_region intron	N/A	ENSP00000348498.3
	NF1	ENST00000431387.8	TSL:1	c.1527+1_1527+4delGTAA		splice_donor splice_region intron	N/A	ENSP00000412921.4

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

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39544

South Asian (SAS) AF: 0.00 AC: 0 AN: 86182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111190

Other (OTH) AF: 0.00 AC: 0 AN: 60316

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:4

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.

Oct 22, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. In silico tools predict the variant to alter splicing and produce an abnormal transcript [SpliceAI: 1.00 (spliceogenicity >=0.2, non-spliceogenicity <0.1)]. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000457536 /PMID: 11258625). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

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

May 28, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1527+4_1527+7delAGTA intronic pathogenic mutation 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 variant was reported in individual(s) with features consistent with 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; Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. 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; Ambry internal data). Other variant(s) impacting the same donor site (c.1527+1G>T) have been identified in individual(s) with features consistent with neurofibromatosis type 1 (NF1) (Hutter S et al. Hum. Genet., 2016 May;135:469-75; Pros E et al. Hum. Mutat., 2008 Sep;29:E173-93; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
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

Other links and lift over

dbSNP: rs1555612294; hg19: chr17-29541603;