17-31156127-G-T

Variant names:

• chr17-31156127-G-T
• rs886039548
• NM_001042492.3:c.204+1G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001042492.3(NF1):​c.204+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: NF1 NM_001042492.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.38
• Publications: 6 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.01690141 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-31156127-G-T is Pathogenic according to our data. Variant chr17-31156127-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 449419.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	c.204+1G>T		splice_donor_variant, intron_variant	Intron 2 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.204+1G>T		splice_donor_variant, intron_variant	Intron 2 of 56		NP_000258.1
NF1	NM_001128147.3	c.204+1G>T		splice_donor_variant, intron_variant	Intron 2 of 14		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.204+1G>T		splice_donor_variant, intron_variant	Intron 2 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152040 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251198 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152040 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74254

African (AFR) AF: 0.00 AC: 0 AN: 41390

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:3

Oct 27, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.204+1G>T variant in NF1 has been reported in 8 individuals with NF1 (Fahso ld 2000, Ars 2003, Wimmer 2007, Pros 2008, Valero 2011, Xu 2014, Pasmant 2015, Z hang 2015) and was absent from large population studies. In addition, this varia nt occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein . In vivo functional studies provide some evidence that the c.204+1G>T variant m ay impact protein function by creating a cryptic splice site that leads to skipp ing of exon 2 or at least a portion of exon 2 (Ars 2003, Wimmer 2007, Pros 2008) . In summary, this variant meets our criteria to be classified as pathogenic for NF1 in an autosomal dominant based upon functional evidence, absence from contr ols, and frequency in probands. -

Mar 15, 2022

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant disrupts a region of the NF1 protein in which other variant(s) (p.Leu43Pro) have been determined to be pathogenic (PMID: 28529006, 31370276; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This sequence change affects a donor splice site in intron 2 of the NF1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 35 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (no rsID available, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with neurofibromatosis type 1 (PMID: 17311297, 21354044). ClinVar contains an entry for this variant (Variation ID: 449419). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 2 (PMID: 17311297). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

May 20, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant predicted to result in an in-frame deletion of exon 2; Deletions involving coding exons of this gene are a known mechanism of disease (Stenson 2014); Observed in individuals with clinical features of neurofibromatosis type 1 (Fahsold 2000, Wimmer 2007, Witkowski 2020); This variant is associated with the following publications: (PMID: 26056819, 17311297, 10712197, 25525159, 30014477, 28717660, 30988082, 21354044, 12807981, 24789688, 25074460, 23913538, 31717729, 32107864) -

Sep 28, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP4, PM2, PS4_moderate, PVS1_moderate -

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

Dec 06, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.204+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 2 of the NF1 gene. This mutation has been detected in multiple patients with a clinical diagnosis of neurofibromatosis type 1 (NF1) and RNA splicing analysis has demonstrated aberrant splicing (Fahsold R et al. Am J Hum Genet. 2000 Mar;66(3):790-818; Wimmer K et al. Hum Mutat. 2007 Jun;28(6):599-612; Pros E et al. Hum Mutat. 2008 Sep;29(9):E173-93; Pasmant E et al. Eur J Hum Genet. 2015 May;23(5):596-601). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		9.4
GERP RS		5.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
Splicevardb		2.0
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: -1

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

Other links and lift over

dbSNP: rs886039548; hg19: chr17-29483145; COSMIC: COSV62191577; COSMIC: COSV62191577;