rs199474752

chr17-31163376-G-Achr17-31163376-G-Cchr17-31163376-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_001042492.3(NF1):c.479G>A(p.Arg160Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R160S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.18

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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-31163376-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 68353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, NF1
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-31163376-G-A is Pathogenic according to our data. Variant chr17-31163376-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 480206.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-31163376-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.479G>A	p.Arg160Lys	missense_variant, splice_region_variant	4/58	ENST00000358273.9
NF1	NM_000267.3	c.479G>A	p.Arg160Lys	missense_variant, splice_region_variant	4/57
NF1	NM_001128147.3	c.479G>A	p.Arg160Lys	missense_variant, splice_region_variant	4/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.479G>A	p.Arg160Lys	missense_variant, splice_region_variant	4/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2017

The c.479G>A variant (also known as p.R160K), located in coding exon 4 of the NF1 gene, results from a G to A substitution at nucleotide position 479. The amino acid change results in arginine to lysine at codon 160, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 4, which makes it likely to have some effect on normal mRNA splicing. This alteration was detected in one individual meeting clinical diagnostic criteria for neurofibromatosis type 1 (NF1) (Ambry internal data), as well as one individual from a prospective cohort of patients with clinical suspicion of NF1 (Pasmant E et al. Eur. J. Hum. Genet., 2015 May;23:596-601). A different nucleotide change at the same position (c.479G>C) has been identified in two individuals meeting NF1 clinical diagnostic criteria and was shown via mRNA analysis to result in exon-skipping (Wimmer K et al. Hum. Mutat., 2007 Jun;28:599-612; Ponti G et al. Hered Cancer Clin Pract, 2011 Aug;9:6). In addition, another different nucleotide change at the same position (c.479G>T) occurred de novo in an individual meeting NF1 diagnostic criteria (Bianchessi D et al. Mol Genet Genomic Med, 2015 Nov;3:513-25; Leiden Open Variation Database- http:// www.LOVD.nl/NF1). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. 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
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
Cadd	Pathogenic	32
Dann	Benign	0.94
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.82	D
MutationTaster	Benign	1.0	D;D;D
ClinPred		0.81	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.62		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.62		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs199474752; hg19: chr17-29490394;