rs1555533875

chr17-31330430-T-Cchr17-31330430-T-G

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.5744T>C(p.Leu1915Pro) 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. 13/21 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. L1915V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.58

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 where missense usually causes diseases, NF1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 17-31330430-T-C is Pathogenic according to our data. Variant chr17-31330430-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 485963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31330430-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.5744T>C	p.Leu1915Pro	missense_variant	39/58	ENST00000358273.9
NF1	NM_000267.3	c.5681T>C	p.Leu1894Pro	missense_variant	38/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.5744T>C	p.Leu1915Pro	missense_variant	39/58	1	NM_001042492.3	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:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 06, 2023	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1894 of the NF1 protein (p.Leu1894Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of neurofibromatosis type 1 (PMID: 31766501; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 485963). 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 with a positive predictive value of 95%. This variant disrupts the p.1894 amino acid residue in NF1. Other variant(s) that disrupt this residue have been observed in individuals with NF1-related conditions (PMID: 27322474), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 01, 2023

Observed in individuals with suspected or clinically diagnosed neurofibromatosis type 1 in the published literature and at an outside laboratory (Melloni et al., 2019; External communication); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23656349, 31766501) -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 09, 2017

The p.L1894P variant (also known as c.5681T>C), located in coding exon 38 of the NF1 gene, results from a T to C substitution at nucleotide position 5681. The leucine at codon 1894 is replaced by proline, an amino acid with similar properties. This alteration was reported as a de novo alteration in a cohort of 1895 patients who were referred for NF1 testing in the Netherlands; however, specific information about the carrier(s) of this alteration was not provided (van Minkelen R et al. Clin. Genet., 2014 Apr;85:318-27). 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	0.56	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;.;D;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.8	D;D;D;.
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;.
Polyphen		1.0	D;D;.;.
Vest4		0.99
MutPred		0.83		Gain of loop (P = 0.0079);.;.;.;
MVP		1.0
MPC		2.9
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs1555533875; hg19: chr17-29657448;