chr17-31221932-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong

The ENST00000431387.8(NF1):c.1724A>G(p.Tyr575Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y575H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

NF1
ENST00000431387.8 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 6.61

Publications

5 publications found

Variant links:

COSMIC-nc: COSV62193369

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 Gene-Disease associations (from GenCC):

neurofibromatosis type 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
neurofibromatosis-Noonan syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
Moyamoya disease
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
hereditary pheochromocytoma-paraganglioma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

NF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 11 benign, 10 uncertain in ENST00000431387.8

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-31221931-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2736517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 17-31221932-A-G is Pathogenic according to our data. Variant chr17-31221932-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 374108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3 link	c.1721+3A>G		splice_region_variant, intron_variant	Intron 15 of 57	ENST00000358273.9	NP_001035957.1	P21359-1
NF1	NM_001128147.3 link	c.1724A>G	p.Tyr575Cys	missense_variant	Exon 15 of 15		NP_001121619.1	P21359-5
NF1	NM_000267.4 link	c.1721+3A>G		splice_region_variant, intron_variant	Intron 15 of 56		NP_000258.1	P21359-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 link	c.1721+3A>G		splice_region_variant, intron_variant	Intron 15 of 57	1	NM_001042492.3	ENSP00000351015.4		P21359-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurofibromatosis, type 1

Pathogenic:8

Nov 16, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3, PS4, PP3, PM2 -

Apr 02, 2020

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 15, 2022

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change falls in intron 15 of the NF1 gene. It does not directly change the encoded amino acid sequence of the NF1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with neurofibromatosis type 1 (PMID: 7981679, 15146469, 16944272, 18546366, 23404336, 26478990). This variant is also known as c.1720+3A>G. ClinVar contains an entry for this variant (Variation ID: 374108). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 15, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 7981679; internal data). For these reasons, this variant has been classified as Pathogenic. -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting+PS3+PS4_Moderate+PP1+PP4+PM6 -

Aug 17, 2022

Medical Genetics, University of Parma

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 17, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Criteria applied: PVS1,PS2,PS4_MOD,PM2_SUP,PP4 -

Apr 08, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: NF1 c.1721+3A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. At least two publications report experimental evidence that this variant affects mRNA splicing, resulting in exon skipping leading to a frameshift (Purandare_1994, Pros_2008). The variant was absent in 225584 control chromosomes (gnomAD). c.1721+3A>G has been reported in the literature in multiple individuals affected with Neurofibromatosis Type 1 (e.g. Purandare_1994, De Luca_2004, Griffiths_2006, Pros_2008.) These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 7981679, 15146469, 16944272, 18546366). ClinVar contains an entry for this variant (Variation ID: 374108). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:3

Jun 28, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Non-canonical splice site variant demonstrated to result in skipping of exon 11 (Violante et al., 2013; Esposito et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis is inconclusive as to whether the variant alters gene splicing; Also known as IVS15+3A>G; This variant is associated with the following publications: (PMID: 19845691, 26478990, 7981679, 23404336, 18546366, 26056819, 15146469, 28008555, 10607834, 16944272, 26969325, 10712197, 16380919, 32352596, 31713330, 31370276, 31776437) -

Aug 06, 2019

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not found in the total gnomAD dataset, and the data is high quality (0/263140 chr). Variant has been found in 6 or more unrelated symptomatic patients, while absent in large general pop studies. Predicted to negatively affect a known splice site. Damaging to protein function(s) relevant to disease mechanism. Inconclusive segregation with disease. -

Jun 22, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP1, PM2_moderate, PVS1 -

Optic nerve glioma;C1861975:Cafe au lait spots, multiple

Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neurofibroma;C1861975:Cafe au lait spots, multiple

Pathogenic:1

Dec 01, 2014

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Juvenile myelomonocytic leukemia

Pathogenic:1

Jul 12, 2022

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Apr 06, 2015

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1721+3A>G intronic pathogenic mutation results from an A to G substitution 3 nucleotides after coding exon 15 in the NF1 gene. This mutation was shown by twoseparate studiestoinduce skipping ofexon11 at the mRNA level, causinga shift in the translational reading frame, leading to premature truncation of the NF1protein(p.Ala548LeufsX13) (PurandareSM, et al. Hum. Mol. Genet. 1994;3(7):1109-15 andPros E, et al. Hum.Mutat. 2008;29(9):E173-93). This mutation has been seen in four individuals who fulfill the NIH diagnostic criteria for NF1 (neurofibromatosis type 1) and in nine individualssuspected of having aNF1 clinical diagnosis. In addition, one of these individuals presented withfeatures of bothNF1 and Noonan syndrome (De Luca A, et al. Am. J. Hum. Genet. 2005;77(6):1092-101,Griffiths S, et al. Fam. Cancer 2007;6(1):21-34,Violante IR, et al. Brain 2013;136(Pt 3):918-25,Purandare SM, et al. Hum. Mol. Genet. 1994;3(7):1109-15,FahsoldR, et al. Am. J. Hum. Genet. 2000;66(3):790-818,andArs E, et al. Hum. Mol. Genet. 2000;9(2):237-47).Based on the available evidence, c.1721+3A>G is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.43

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Benign

0.051

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.37

M_CAP

Benign

0.021

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.85

PhyloP100

6.6

PROVEAN

Benign

1.2

REVEL

Benign

0.18

Sift

Benign

0.057

Sift4G

Benign

0.15

Vest4

0.47

MutPred

0.33

Gain of catalytic residue at I573 (P = 0.1473);

MVP

0.64

ClinPred

0.70

GERP RS

5.8

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.55

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.55

Position offset: -1

DS_DL_spliceai

0.49

Position offset: -3

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over