rs267606604

chr17-31336328-A-Gchr17-31336328-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_001042492.3(NF1):c.6007-5A>G variant causes a splice region, 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: NF1 NM_001042492.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9975
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: -0.0320

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-31336328-A-G is Pathogenic according to our data. Variant chr17-31336328-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31336328-A-G is described in Lovd as [Pathogenic]. Variant chr17-31336328-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.6007-5A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000358273.9
NF1	NM_000267.3	c.5944-5A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.6007-5A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 26, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 25, 2023	Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 7981692, 11704931). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 359). This variant has been observed in individuals with neurofibromatosis type 1 and/or NF1-related conditions (PMID: 7981692, 10712197, 11704931, 18546366, 24789688; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 39 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Medical Genomics Laboratory, Department of Genetics UAB	Jan 20, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 22, 2020

Non-canonical splice site variant demonstrated to result in loss-of-function (Kaufmann 2001, Pros 2008, Xu 2014, Giugliano 2019, Wimmer 2020); In silico analysis supports a deleterious effect on splicing; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 31370276, 19221814, 24789688, 18546366, 32126153, 11704931, 10712197, 14569132, 7981692) -

Neurofibromatosis, familial spinal Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2001

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2021

The c.5944-5A>G intronic pathogenic mutation results from an A to G substitution 5 nucleotides upstream from coding exon 40 in the NF1 gene. This mutation has been reported in several individuals with a clinical or suspected diagnosis of neurofibromatosis type 1 (Ainsworth P et al. Hum Mol Genet, 1994 Jul;3:1179-81; Fahsold R et al. Am J Hum Genet, 2000 Mar;66:790-818; Kaufmann D et al. Am J Hum Genet, 2001 Dec;69:1395-400; Xu W et al. Int J Mol Med, 2014 Jul;34:53-60). In addition, this alteration results in the insertion of four nucleotides between NF1 exons 39 and 40, leading to creation of a premature stop codon (Ainsworth P et al. Hum Mol Genet, 1994 Jul;3:1179-81; Kaufmann D et al. Am J Hum Genet, 2001 Dec;69:1395-400; Xu W et al. Int J Mol Med, 2014 Jul;34:53-60; Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	22
Dann	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs267606604; hg19: chr17-29663346;