rs565708398

chr17-31349143-A-Gchr17-31349143-A-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM1 PP2 BP4_Strong BP6 BS2

The NM_001042492.3(NF1):c.7213A>G(p.Ile2405Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,605,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. I2405S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:4
• Conservation: PhyloP100: 6.79

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_benign. Variant got -6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_001042492.3
• PP2: Missense variant where missense usually causes diseases, NF1
• BP4: Computational evidence support a benign effect (MetaRNN=0.051487297).
• BP6: Variant 17-31349143-A-G is Benign according to our data. Variant chr17-31349143-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 186162.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=4}. Variant chr17-31349143-A-G is described in Lovd as [Benign].
• BS2: High AC in GnomAdExome at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.7213A>G	p.Ile2405Val	missense_variant	49/58	ENST00000358273.9
NF1	NM_000267.3	c.7150A>G	p.Ile2384Val	missense_variant	48/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.7213A>G	p.Ile2405Val	missense_variant	49/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000336 AC: 8 AN: 238068 Hom.: 0 AF XY: 0.0000234 AC XY: 3 AN XY: 128274

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000282

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.0000117 AC: 17 AN: 1452866 Hom.: 0 Cov.: 32 AF XY: 0.00000970 AC XY: 7 AN XY: 721932

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.000207

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000361

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74492

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 27, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 29, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Neurofibromatosis, type 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2384 of the NF1 protein (p.Ile2384Val). This variant is present in population databases (rs565708398, gnomAD 0.009%). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 186162). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 08, 2015	The p.I2405V variant (also known as c.7213A>G), located in coding exon 49 of the NF1 gene, results from an A to G substitution at nucleotide position 7213. The isoleucine at codon 2405 is replaced by valine, an amino acid with highly similar properties. 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.<span style="background-color:initial">To date, this alteration has been detected with an allele frequency of approximately 0.004% (greater than 55000 alleles tested) in our clinical cohort.<span style="background-color:initial"><span style="background-color:initial">This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. <span style="background-color:initial">Since supporting evidence is limited at this time, the clinical significance of<span style="background-color:initial">p.I2405V<span style="background-color:initial">remains unclear. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 20, 2021

DNA sequence analysis of the NF1 gene demonstrated a sequence change, c.7150A>G, in exon 48 that results in an amino acid change, p.Ile2384Val. This sequence change has been described in the gnomAD database with a frequency of 0.012% in the Latino/Admixed American subpopulation (dbSNP rs565708398).The p.Ile2384Val change affects a poorly conserved amino acid residue located in a domain of the NF1 protein that is known to be functional. The p.Ile2384Val substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequences change does not appear to have been previously described in individuals with NF1-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Ile2384Val change remains unknown at this time. -

Neurofibromatosis, type 1;C0349639:Juvenile myelomonocytic leukemia;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2017

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 02, 2023

This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	21
Dann	Benign	0.91
DEOGEN2	Benign	0.39	T;.;T
Eigen	Benign	-0.22
Eigen_PC	Benign	0.021
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.051	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.34	N;.;.
MutationTaster	Benign	0.61	N;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.45	N;N;N
REVEL	Benign	0.060
Sift	Benign	0.23	T;T;T
Sift4G	Benign	0.37	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.16
MutPred		0.32		Loss of catalytic residue at V2406 (P = 0.1421);.;.;
MVP		0.31
MPC		0.43
ClinPred		0.13	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.052
gMVP		0.25

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: rs565708398; hg19: chr17-29676161; COSMIC: COSV62194004; COSMIC: COSV62194004;