17-31223470-A-G

Position:

• chr17-31223470-A-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP2 PP5_Very_Strong

The NM_001042492.3(NF1):​c.1748A>G​(p.Lys583Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 5.31

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 13 ACMG points.

• PM1: In a helix (size 19) in uniprot entity NF1_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_001042492.3
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP5: Variant 17-31223470-A-G is Pathogenic according to our data. Variant chr17-31223470-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31223470-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.1748A>G	p.Lys583Arg	missense_variant	16/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.1748A>G	p.Lys583Arg	missense_variant	16/57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.1748A>G	p.Lys583Arg	missense_variant	16/58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460616 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726674

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jan 17, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 26, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	May 24, 2023	PS4, PM1, PM2, PM5, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 02, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 583 of the NF1 protein (p.Lys583Arg). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 9 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10712197, 16944272, 17726231, 18041031, 21354044, 27074763, 27322474, 31370276). ClinVar contains an entry for this variant (Variation ID: 68306). 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 not expected to disrupt NF1 protein function with a negative predictive value of 95%. Studies have shown that this missense change results in the activation of a cryptic splice site in exon 16 (PMID: 18041031, 27322474; Invitae). This variant disrupts a region of the NF1 protein in which other variant(s) (p.Leu578Pro) have been determined to be pathogenic (PMID: 12746402, 16479075, 17426081, 23668869, 25211147). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Mar 18, 2024	Criteria applied: PS3,PS4_MOD,PM4,PM2_SUP -

not provided Pathogenic:2 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 23, 2017	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2023	RNA studies indicate this variant leads to the creation of a cryptic splice site and the loss of 27 base pairs (Brinckmann et al., 2007; Valero et al., 2011, Evans et al., 2016) within the critical GTPase activating protein domain (Luo et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22155606, 16944272, 24803665, 17726231, 28068329, 10712197, 18041031, 27322474, 27074763, 25541118, 21354044, 30308447, 31370276, 34418705, 34308104, 25486365) -

Café-au-lait macules with pulmonary stenosis Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Oct 04, 2024

PS4, PM1, PM2, PM5, PP4 -

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 06, 2024

The p.K583R pathogenic mutation (also known as c.1748A>G), located in coding exon 16 of the NF1 gene, results from an A to G substitution at nucleotide position 1748. The lysine at codon 583 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported de novo in an individual with features of neurofibromatosis type 1 (Tsipi M et al. J. Neurol. Sci., 2018 12;395:95-105). This variant has also been identified in multiple individuals meeting diagnostic criteria for NF1 and has been shown to result in abnormal splicing (Fahsold R et al. Am. J. Hum. Genet., 2000 Mar;66:790-818; Brinckmann A et al. Electrophoresis, 2007 Dec;28:4295-301; Bendova S et al. J. Mol. Neurosci., 2007;31:273-9; Evans DG et al. EBioMedicine, 2016 May;7:212-20). Based on the available evidence, this variant is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;.;T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N;N;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.41	N;N;N
REVEL	Benign	0.026
Sift	Benign	0.35	T;T;T
Sift4G	Benign	0.17	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.71
MutPred		0.33		Loss of methylation at K583 (P = 0.0026);Loss of methylation at K583 (P = 0.0026);.;
MVP		0.62
MPC		0.56
ClinPred		0.60	D
GERP RS		5.3
Varity_R		0.093
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.95		Position offset: 1
DS_AL_spliceai		0.79		Position offset: -26

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

Publications

LitVar

Other links and lift over

dbSNP: rs199474760; hg19: chr17-29550488; COSMIC: COSV62211399; COSMIC: COSV62211399;