rs1555614652

Variant names:

• chr17-31230925-G-A
• rs1555614652
• NM_001042492.3:c.3197G>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

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 Likely pathogenic (★★).

• 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, multiple submitters, no conflicts P:3
• 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 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the NF1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 399 curated pathogenic missense variants (we use a threshold of 10). The gene has 143 curated benign missense variants. Gene score misZ: 6.5427 (above the threshold of 3.09). Trascript score misZ: 8.4054 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 [Likely_pathogenic]. Clinvar id is 449425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31230925-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.3197G>A	p.Arg1066Lys	missense_variant, splice_region_variant	Exon 24 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.3197G>A	p.Arg1066Lys	missense_variant, splice_region_variant	Exon 24 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.3197G>A	p.Arg1066Lys	missense_variant, splice_region_variant	Exon 24 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:1

Aug 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 individuals with clinical features of NF1-related conditions (PMID: 21520333; Invitae). 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 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 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. -

not provided Pathogenic:1

Aug 03, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 14, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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;.
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;