rs1131691066

Positions:

• chr17-31201024-G-A
• chr17-31201024-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001042492.3(NF1):​c.1063-13G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.880

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-31201024-G-A is Pathogenic according to our data. Variant chr17-31201024-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31201024-G-A is described in Lovd as [Pathogenic]. Variant chr17-31201024-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.1063-13G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.1063-13G>A		splice_polypyrimidine_tract_variant, intron_variant			NP_000258.1
NF1	NM_001128147.3	c.1063-13G>A		splice_polypyrimidine_tract_variant, intron_variant			NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.1063-13G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001042492.3	ENSP00000351015	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	UAB Medical Genomics Laboratory, UAB Medicine	Jan 20, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 11, 2023	This sequence change falls in intron 9 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 may result in an absent or disrupted 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: 10712197, 21354044). ClinVar contains an entry for this variant (Variation ID: 428940). Studies have shown that this variant results in the insertion of 11 nucleotides and introduces a premature termination codon (PMID: 18546366). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2022

The c.1063-13G>A intronic pathogenic mutation results from a G to A substitution 13 nucleotides upstream from coding exon 10 in the NF1 gene. This variant has been detected in individuals affected with neurofibromatosis type 1 (Fahsold R et al. Am. J. Hum. Genet., 2000 Mar;66:790-818; Pros E et al. Hum. Mutat., 2008 Sep;29:E173-93; Valero MC et al. J Mol Diagn, 2011 Mar;13:113-22; Wimmer K et al. Hum Mutat, 2020 06;41:1145-1156). Functional studies showed that this alteration resulted in the insertion of 11 nucleotides into the intron (r.1062_1063ins1063-11_1063-1) predicted to generate an alternate protein product (Pros E et al. Hum. Mutat. 2008; 29:E173-93). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This nucleotide position is well conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 21, 2014

The c.1063-13G>A intronic variant results from a G to A substitution 13 nucleotides upstream from coding exon 10 in the NF1 gene. This alteration was first reported in 1 out of 500 unrelated patients with neurofibromatosis type 1 (NF1) (Fahsold R et al. Am. J. Hum. Genet. 2000; 66:790-818). A functional study analyzed mRNA products and found this alteration created a cryptic 3' splice site which resulted in the insertion of 11 nucleotides into the intron (r.1062_1063ins1063-11_1063-1) predicted to generate an alternate protein product(Pros E et al. Hum. Mutat. 2008; 29:E173-93).This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. This nucleotide position is well conserved through mammals in available vertebrate species; however, A is the reference nucleotide in the shrew. Using the BDGP and ESEfinder splice site prediction tools, this alteration creates a new alternate splice acceptor site.Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	23
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.98		Position offset: 2
DS_AL_spliceai		0.89		Position offset: 13

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

Publications

LitVar

Other links and lift over

dbSNP: rs1131691066; hg19: chr17-29528042;