17-31223567-G-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong

The NM_001042492.3(NF1):c.1845G>T(p.Lys615Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000686 in 1,458,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K615K) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

NF1
NM_001042492.3 missense, splice_region

Scores

Splicing: ADA: 0.9999

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 4.94

Variant links:

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]

NF1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM1

In a helix (size 24) in uniprot entity NF1_HUMAN there are 6 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 where missense usually causes diseases, NF1

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 17-31223567-G-T is Pathogenic according to our data. Variant chr17-31223567-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31223567-G-T is described in Lovd as [Pathogenic]. Variant chr17-31223567-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3 linkuse as main transcript	c.1845G>T	p.Lys615Asn	missense_variant, splice_region_variant	16/58	ENST00000358273.9
NF1	NM_000267.3 linkuse as main transcript	c.1845G>T	p.Lys615Asn	missense_variant, splice_region_variant	16/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9 linkuse as main transcript	c.1845G>T	p.Lys615Asn	missense_variant, splice_region_variant	16/58	1	NM_001042492.3	P1	P21359-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458596

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725778

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 16, 2022	BP4, PP4, PM2, PVS1_strong -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 13, 2018	This variant is denoted NF1 c.1845G>T at the cDNA level. Located at the last nucleotide of exon 16, it disrupts a natural splice site and causes abnormal splicing. Studies have demonstrated that this variant results in skipping of exon 16 (referred to as exon 12a in published reports) and/or exons 15 and 16 (exons 11 and 12a) (Pros 2008, Sabbagh 2013). This variant has been observed in several individuals with neurofibromatosis type 1 (Pros 2008, Onitilo 2013, Sabbagh 2013, Duat Rodriguez 2015, Santoro 2017). Although the substitution results in the change of a Lysine to an Asparagine at codon 615 and is called p.Lys615Asn (K615N) in the literature, we are only using the nucleotide nomenclature to refer to the variant since the defect is determined to be one of splicing rather than a resulting missense variant. NF1 c.1845G>T was not observed in large population cohorts (Lek 2016). In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider NF1 Lys615Asn to be a likely pathogenic variant. -

Neurofibromatosis, type 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 25, 2022

For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 16 and introduces a premature termination codon (PMID: 18546366). The resulting mRNA is expected to undergo nonsense-mediated decay. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 428956). This missense change has been observed in individual(s) with neurofibromatosis type 1 (PMID: 18546366, 23322702, 25541118, 28422438, 29673180). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 615 of the NF1 protein (p.Lys615Asn). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2015

Thec.1845G>Tpathogenic mutation (also known as p.K615N) islocated in coding exon 16 of theNF1gene. This pathogenic mutation results from a G to T substitution at nucleotide position 1845. The amino acid change results in lysine to asparagine at codon 615, an amino acid with similar properties. However, this change occurs in the last base pair of exon 16 which makes it likely to have some effect on normal mRNA splicing.This amino acid position is highly conserved in available vertebrate species. In one study, this mutation wasclassifiedas a type I splicesite mutation affecting the canonical 3'splice site based on mRNA functional studies, which ultimately showed that the mutation resulted inan out of frame deletion causing exon 16 to be skipped (Pros E, Hum. Mutat. 2008 Sep; 29(9):E173-93).In a seperate publication, this mutation was seenin anindividual fromthe french NF1 cohort who was clinically diagnosed with NF1. In addition,RNA studies in this publicationshowed that this splice site mutation creates two transcripts:one whichskips exons 15 and 16and the other that skips exon 16(Sabbagh A, Hum. Mutat. 2013;34(11):1510-8).In addition, this mutation was seen in an individual who met NIH clinical criteria for NF1 and also sufferedfromsplenic infarction, a large benignhepatic cyst, a large uterine fibroma, and iron deficiency (Onitilo AA, et al. Am. J. Med. Genet. A 2013;161A(2):389-92).Based on the supporting evidence, c.1845G>Tis interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

D;.;T

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.30

T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.8

L;L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-2.8

D;D;N

REVEL

Benign

0.13

Sift

Benign

0.11

T;T;D

Sift4G

Benign

0.071

T;T;T

Polyphen

0.40

B;D;.

Vest4

0.81

MutPred

0.29

Loss of ubiquitination at K615 (P = 0.0381);Loss of ubiquitination at K615 (P = 0.0381);.;

MVP

0.46

MPC

0.81

ClinPred

0.92

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.41

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.88

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.88

Position offset: 0

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over