rs1555534307

Variant names:

• chr17-31334376-GTTTTTGCGGGGGAGTGGGAGTGGGTTATACCTGTGTACACACACATAAATGTACATTAACTCTACATAAATTTGAAAGCCTGAGGAGAGATGAGATGATACACCAATGTTAATACAGTTTTCATTTTGTGGTGATGCTTTCCTTTTACCAAACTTTCTATGATTACCACATTTCCTTTTATAATGAGAATAAAACAACTTTTTAACAAGAAAGGACTAAAATGGAGGAAAATAAGACAAAACTTTTCAAAAATTGGCTTACTGGCTTTTAAAATTACTTTCTTCAAGGACTGTTCTTTCTTCGCCTCTACAAAAATATATTTGCCAAGTGTCTTTTCTCCAGGCCTGATTCTAGGTAATAGTCTTTACCTTTTACCATTTTTTCCCCGAATTCTTTATGTTAAATAATTGTTGATGTGATTTTCATTGACCATCACATGCTAATAGTGTATTTTTTTCCAGGTATTGAATTGAAACACCTTTGTTTGGAATACATGACTCCATGGCTGTCAAATCTAGTTCGTTTTTGCAAGCATAATGATGATGCCAAACGACAAAGAGTTACTGCTATTCTTGACAAGCTGATAACAATGACCATCAATGAAAAACAGATGTACCCATCTATTCAAGCAAAAATATGGGGAAGCCTTGGGCAGGTATTGAGTTTGCTCAAATATTTATCTAGTATCTCCTTTGTGCACATATTTATCTGGTGCCACATTGGGCAAAGCACTGCGCTAGACACTAGGGATAGAGTTGTAAAAAACACAGTTTCCTCCTTCAGAAAGCATGTAGACACTCACCCAGCTCTTCATCTGGTTCAAAATTGTAAATGTCTAGTGCATGTCTCAGAGCCAGAGAAAAGCTAGTTATTTGCACAGTCTCCTTCAAGGCATAAT-G
• rs1555534307
• NM_001042492.3:c.5813-460_6006+244del

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_001042492.3(NF1):​c.5813-460_6006+244del variant causes a exon loss, splice acceptor, splice donor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 30)
• Consequence: NF1 NM_001042492.3 exon_loss, splice_acceptor, splice_donor, splice_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.700
• Publications: 0 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: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PP5: Variant 17-31334376-GTTTTTGCGGGGGAGTGGGAGTGGGTTATACCTGTGTACACACACATAAATGTACATTAACTCTACATAAATTTGAAAGCCTGAGGAGAGATGAGATGATACACCAATGTTAATACAGTTTTCATTTTGTGGTGATGCTTTCCTTTTACCAAACTTTCTATGATTACCACATTTCCTTTTATAATGAGAATAAAACAACTTTTTAACAAGAAAGGACTAAAATGGAGGAAAATAAGACAAAACTTTTCAAAAATTGGCTTACTGGCTTTTAAAATTACTTTCTTCAAGGACTGTTCTTTCTTCGCCTCTACAAAAATATATTTGCCAAGTGTCTTTTCTCCAGGCCTGATTCTAGGTAATAGTCTTTACCTTTTACCATTTTTTCCCCGAATTCTTTATGTTAAATAATTGTTGATGTGATTTTCATTGACCATCACATGCTAATAGTGTATTTTTTTCCAGGTATTGAATTGAAACACCTTTGTTTGGAATACATGACTCCATGGCTGTCAAATCTAGTTCGTTTTTGCAAGCATAATGATGATGCCAAACGACAAAGAGTTACTGCTATTCTTGACAAGCTGATAACAATGACCATCAATGAAAAACAGATGTACCCATCTATTCAAGCAAAAATATGGGGAAGCCTTGGGCAGGTATTGAGTTTGCTCAAATATTTATCTAGTATCTCCTTTGTGCACATATTTATCTGGTGCCACATTGGGCAAAGCACTGCGCTAGACACTAGGGATAGAGTTGTAAAAAACACAGTTTCCTCCTTCAGAAAGCATGTAGACACTCACCCAGCTCTTCATCTGGTTCAAAATTGTAAATGTCTAGTGCATGTCTCAGAGCCAGAGAAAAGCTAGTTATTTGCACAGTCTCCTTCAAGGCATAAT-G is Pathogenic according to our data. Variant chr17-31334376-GTTTTTGCGGGGGAGTGGGAGTGGGTTATACCTGTGTACACACACATAAATGTACATTAACTCTACATAAATTTGAAAGCCTGAGGAGAGATGAGATGATACACCAATGTTAATACAGTTTTCATTTTGTGGTGATGCTTTCCTTTTACCAAACTTTCTATGATTACCACATTTCCTTTTATAATGAGAATAAAACAACTTTTTAACAAGAAAGGACTAAAATGGAGGAAAATAAGACAAAACTTTTCAAAAATTGGCTTACTGGCTTTTAAAATTACTTTCTTCAAGGACTGTTCTTTCTTCGCCTCTACAAAAATATATTTGCCAAGTGTCTTTTCTCCAGGCCTGATTCTAGGTAATAGTCTTTACCTTTTACCATTTTTTCCCCGAATTCTTTATGTTAAATAATTGTTGATGTGATTTTCATTGACCATCACATGCTAATAGTGTATTTTTTTCCAGGTATTGAATTGAAACACCTTTGTTTGGAATACATGACTCCATGGCTGTCAAATCTAGTTCGTTTTTGCAAGCATAATGATGATGCCAAACGACAAAGAGTTACTGCTATTCTTGACAAGCTGATAACAATGACCATCAATGAAAAACAGATGTACCCATCTATTCAAGCAAAAATATGGGGAAGCCTTGGGCAGGTATTGAGTTTGCTCAAATATTTATCTAGTATCTCCTTTGTGCACATATTTATCTGGTGCCACATTGGGCAAAGCACTGCGCTAGACACTAGGGATAGAGTTGTAAAAAACACAGTTTCCTCCTTCAGAAAGCATGTAGACACTCACCCAGCTCTTCATCTGGTTCAAAATTGTAAATGTCTAGTGCATGTCTCAGAGCCAGAGAAAAGCTAGTTATTTGCACAGTCTCCTTCAAGGCATAAT-G is described in ClinVar as [Pathogenic]. Clinvar id is 217091.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.5813-460_6006+244del		exon_loss_variant, splice_acceptor_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 40 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.5750-460_5943+244del		exon_loss_variant, splice_acceptor_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 39 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.5813-461_6006+243del		exon_loss_variant, splice_acceptor_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 40 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 30

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:1

-

UAB Medical Genomics Laboratory, UAB Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.70

Splicing

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

Other links and lift over

dbSNP: rs1555534307; hg19: chr17-29661394;