rs1555614462

Positions:

• chr17-31229974-G-A
• chr17-31229974-G-C
• chr17-31229974-G-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001042492.3(NF1):​c.2990G>A​(p.Arg997Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense, splice_region
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• 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 15 ACMG points.

• PM1: In a helix (size 10) in uniprot entity NF1_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_001042492.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NF1. . Gene score misZ 6.5427 (greater than the threshold 3.09). Trascript score misZ 8.4054 (greater than threshold 3.09). GenCC has associacion of gene with neurofibromatosis, familial spinal, hereditary pheochromocytoma-paraganglioma, neurofibromatosis type 1, Watson syndrome, neurofibromatosis-Noonan syndrome, Moyamoya disease, familial ovarian cancer.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 17-31229974-G-A is Pathogenic according to our data. Variant chr17-31229974-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 654334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31229974-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.2990G>A	p.Arg997Lys	missense_variant, splice_region_variant	22/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.2990G>A	p.Arg997Lys	missense_variant, splice_region_variant	22/57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.2990G>A	p.Arg997Lys	missense_variant, splice_region_variant	22/58	1	NM_001042492.3	ENSP00000351015	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 23, 2018	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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this nucleotide change can result in skipping of exon 22. Exon 22 is also known as exon 17 in the literature (PMID: 23913538). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individuals affected with neurofibromatosis type 1 (PMID: 23913538, 29673180, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with lysine at codon 997 of the NF1 protein (p.Arg997Lys). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and lysine. This variant also falls at the last nucleotide of exon 22 of the NF1 coding sequence, which is part of the consensus splice site for this exon. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 03, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28068329, 25486365, 2121369, 29673180, 23913538, Kiraz_2023, 35121649) -

Juvenile myelomonocytic leukemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 20, 2023

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 07, 2019

The c.2990G>A pathogenic mutation (also known as p.R997K), located in coding exon 22 of the NF1 gene, results from a G to A substitution at nucleotide position 2990. The amino acid change results in arginine to lysine at codon 997, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 22, which makes it likely to have some effect on normal mRNA splicing. This alteration has been identified in a French NF1 cohort and is reported to result in exon skipping (Sabbagh A et al. Hum. Mutat., 2013 Nov;34:1510-8). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, a slight weakening in the native splice donor site efficiency and a weakening in the native splice donor site efficiency are predicted, respectively. Based on the available evidence, this variant is classified as a pathogenic mutation. . -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.00028	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;.;T
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.5	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.27
Sift	Benign	0.35	T;T;T
Sift4G	Benign	0.078	T;T;T
Polyphen		0.98	D;P;.
Vest4		0.69
MutPred		0.43		Gain of ubiquitination at R997 (P = 0.0146);Gain of ubiquitination at R997 (P = 0.0146);.;
MVP		0.70
MPC		1.6
ClinPred		0.92	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.37
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.36		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: rs1555614462; hg19: chr17-29556992;