rs1555614652

Positions:

• chr17-31230925-G-A
• chr17-31230925-G-C
• chr17-31230925-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP2 PP3_Strong PP5

The NM_001042492.3(NF1):​c.3197G>A​(p.Arg1066Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1066T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.73

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-31230925-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 457629.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
• 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, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-31230925-G-A is Pathogenic according to our data. Variant chr17-31230925-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 449425.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}. Variant chr17-31230925-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.3197G>A	p.Arg1066Lys	missense_variant, splice_region_variant	24/58	ENST00000358273.9
NF1	NM_000267.3	c.3197G>A	p.Arg1066Lys	missense_variant, splice_region_variant	24/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.3197G>A	p.Arg1066Lys	missense_variant, splice_region_variant	24/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 03, 2017

The R1066K variant has been reported in the Human Gene Mutation Database in association with neurofibromatosis type 1; however, the variant was obtained via personal communication and no additional information is available (Stenson et al., 2014). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). R1066K is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position within the GTPase activating domain that is conserved across species. In silico analysis predicts R1066K results in the loss of the natural splice donor site of intron 24. However, in the absence of RNA/functional studies, the actual effect of this sequence change is unknown. In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 2024

The c.3197G>A variant (also known as p.R1066K), located in coding exon 24 of the NF1 gene, results from a G to A substitution at nucleotide position 3197. The amino acid change results in arginine to lysine at codon 1066, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 24, which makes it likely to have some effect on normal mRNA splicing. This variant was reported in individuals with features consistent with Neurofibromatosis type 1 (van Minkelen R et al. Clin Genet, 2014 Apr;85:318-27). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Neurofibromatosis, type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 1066 of the NF1 protein (p.Arg1066Lys). This variant also falls at the last nucleotide of exon 24, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of NF1-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 449425). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.3197G>C nucleotide in the NF1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;.;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Uncertain	0.59	D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.9	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-2.3	N;N;N
REVEL	Pathogenic	0.71
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.065	T;T;T
Polyphen		0.89	P;P;.
Vest4		0.43
MutPred		0.48		Gain of ubiquitination at R1066 (P = 0.0128);Gain of ubiquitination at R1066 (P = 0.0128);.;
MVP		0.67
MPC		1.6
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.53
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.92		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: rs1555614652; hg19: chr17-29557943; COSMIC: COSV62193179; COSMIC: COSV62193179;