rs1555611039

Positions:

• chr17-31201155-TTAAGG-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.1183_1185+2del variant causes a splice donor, coding sequence change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. F394F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 splice_donor, coding_sequence
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.56

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 0.0071596242 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 17-31201155-TTAAGG-T is Pathogenic according to our data. Variant chr17-31201155-TTAAGG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 457519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.1183_1185+2del		splice_donor_variant, coding_sequence_variant	10/58	ENST00000358273.9
NF1	NM_000267.3	c.1183_1185+2del		splice_donor_variant, coding_sequence_variant	10/57
NF1	NM_001128147.3	c.1183_1185+2del		splice_donor_variant, coding_sequence_variant	10/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.1183_1185+2del		splice_donor_variant, coding_sequence_variant	10/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 26, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 05, 2017	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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). This variant has not been reported in the literature in individuals with a NF1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change deletes the last three nucleotides in exon 10 and affects a donor splice site in intron 10 of the NF1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555611039; hg19: chr17-29528173;