chr17-31223455-T-C

Position:

• chr17-31223455-T-C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The ENST00000358273.9(NF1):​c.1733T>C​(p.Leu578Pro) 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. 12/21 in silico tools predict a damaging outcome for this variant. 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. L578R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 ENST00000358273.9 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.41

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 17 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in ENST00000358273.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-31223455-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.897
• PP5: Variant 17-31223455-T-C is Pathogenic according to our data. Variant chr17-31223455-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 485956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31223455-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.1733T>C	p.Leu578Pro	missense_variant	16/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.1733T>C	p.Leu578Pro	missense_variant	16/57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.1733T>C	p.Leu578Pro	missense_variant	16/58	1	NM_001042492.3	ENSP00000351015	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 20, 2023	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 578 of the NF1 protein (p.Leu578Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with neurofibromatosis type 1 (PMID: 16479075, 17426081). ClinVar contains an entry for this variant (Variation ID: 485956). 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. This variant disrupts the p.Leu578 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12746402, 23668869, 25211147). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Medical Genetics, University of Parma	Aug 17, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Nov 11, 2021	- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2016

The p.L578P variant (also known as c.1733T>C), located in coding exon 16 of the NF1 gene, results from a T to C substitution at nucleotide position 1733. The leucine at codon 578 is replaced by proline, an amino acid with similar properties. This alteration has been reported in two individuals meeting diagnostic criteria for neurofibromatosis type 1 (Jeong SY et al. J. Korean Med. Sci., 2006 Feb;21:107-12; Bausch B et al. J. Clin. Endocrinol. Metab., 2007 Jul;92:2784-92). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6501 samples (13002 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 175000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D;.;T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.2	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.6	D;D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0080	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.99
MutPred		0.69		Gain of loop (P = 3e-04);Gain of loop (P = 3e-04);.;
MVP		0.96
MPC		1.8
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.87
gMVP		0.95

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: rs199474774; hg19: chr17-29550473; COSMIC: COSV62197311; COSMIC: COSV62197311;