17-31330454-C-A

Position:

• chr17-31330454-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP2 PP3_Moderate PP5

The NM_001042492.3(NF1):​c.5768C>A​(p.Thr1923Lys) variant causes a missense 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. 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. T1923R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 7.47

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-31330454-C-G is described in Lovd as [Likely_pathogenic].
• 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: MetaRNN computational evidence supports a deleterious effect, 0.925
• PP5: Variant 17-31330454-C-A is Pathogenic according to our data. Variant chr17-31330454-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 945629.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.5768C>A	p.Thr1923Lys	missense_variant	39/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.5705C>A	p.Thr1902Lys	missense_variant	38/57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.5768C>A	p.Thr1923Lys	missense_variant	39/58	1	NM_001042492.3	ENSP00000351015	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 09, 2022	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Thr1902 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25074460; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NF1 protein function. ClinVar contains an entry for this variant (Variation ID: 945629). This missense change has been observed in individual(s) with clinical features of neurofibromatosis type 1 (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 1902 of the NF1 protein (p.Thr1902Lys). -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 06, 2022

The p.T1902K variant (also known as c.5705C>A), located in coding exon 38 of the NF1 gene, results from a C to A substitution at nucleotide position 5705. The threonine at codon 1902 is replaced by lysine, an amino acid with similar properties. This alteration has been identified in multiple individuals with a clinical diagnosis of neurofibromatosis type 1 (NF1) (Ambry internal data; Garibotto F et al. Front Oncol, 2020 Jun;10:795). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 15, 2019

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D;.;D;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.2	D;D;D;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;.
Polyphen		1.0	D;D;.;.
Vest4		0.84
MutPred		0.57		Gain of ubiquitination at T1923 (P = 0.0185);.;.;.;
MVP		0.99
MPC		2.5
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.90
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs786203824; hg19: chr17-29657472;