rs886039548

Positions:

• chr17-31156127-G-A
• chr17-31156127-G-C
• chr17-31156127-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001042492.3(NF1):​c.204+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,364 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• 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:10
• Conservation: PhyloP100: 9.38

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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.016784038 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-A is Pathogenic according to our data. Variant chr17-31156127-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31156127-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.204+1G>A		splice_donor_variant, intron_variant		ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.204+1G>A		splice_donor_variant, intron_variant			NP_000258.1
NF1	NM_001128147.3	c.204+1G>A		splice_donor_variant, intron_variant			NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.204+1G>A		splice_donor_variant, intron_variant		1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461364 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727020

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The splice site variant c.204+1G>A in NF1 gene has been reported in the literature in individuals affected with neurofibromatosis type 1 (Zhang J et.al.,2015). This variant has been reported to the ClinVar database as Pathogenic. The c.204+1G>A variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The variant affects an invariant splice nucleotide and is expected to cause loss of function .Donor and acceptor splice site variants typically lead to a loss of protein function and loss-of-function variants in NF1 are known to be pathogenic (Fahsold R et.al.,2000). For these reasons, this variant has been classified as Pathogenic. -
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	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Aug 24, 2022	ACMG classification criteria: PVS1 strong, PS4 moderated, PM2 moderated, PM6 moderated -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with neurofibromatosis type 1 (NF1) (PMID: 12807981, 18546366, 21520333, 26056819). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 265442). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 2 (Invitae). 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. For these reasons, this variant has been classified as Pathogenic. -
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	Genome-Nilou Lab	Mar 15, 2022	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 03, 2024	PP4, PM2, PS4_moderate, PVS1_strong -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2024	Canonical splice site variant predicted to result in an in-frame deletion/insertion of a critical region; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12807981, 25525159, 21354044, 18546366, 19061981, 26056819, 25541118, 29415745, 23913538, 30908848, 33877690, 33057194, 35982159) -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 19, 2019

The NF1 c.204+1G>A variant (rs886039548), also known as IVS2+1G>A, is reported in the literature in multiple individuals affected with neurofibromatosis type I (Ars 2003, Pros 2008, Zhang 2015). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 265442), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant disrupts the canonical splice donor site of intron 2, which is likely to negatively impact gene function. Based on available information, this variant is considered to be pathogenic. References: Ars E et al. Recurrent mutations in the NF1 gene are common among neurofibromatosis type 1 patients. J Med Genet. 2003 40(6):e82. Pros E et al. Nature and mRNA effect of 282 different NF1 point mutations: focus on splicing alterations Hum Mutat. 2008 Sep;29(9):E173-93. Zhang J et al. Molecular Characterization of NF1 and Neurofibromatosis Type 1 Genotype-Phenotype Correlations in a Chinese Population. Sci Rep. 2015 5:11291. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 25, 2021

The c.204+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 2 of the NF1 gene. This mutation has been identified in multiple individuals with a clinical diagnosis of neurofibromatosis type 1 (Zhang J et al. Sci Rep. 2015 Jun;5:11291; Leskelä HV et al. Bone. 2009 Feb;44:243-50; Ambry internal data). In addition, RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Another alteration impacting the same donor site (c.204+1G>T) has been detected in multiple individuals with neurofibromatosis type 1 and reported to result in aberrant splicing (Fahsold R et al. Am J Hum Genet, 2000 Mar;66:790-818; Wimmer K et al. Hum Mutat, 2007 Jun;28:599-612; Pros E et al. Hum Mutat, 2008 Sep;29:E173-93). c.204+1G>A is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
GERP RS		5.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
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

Publications

LitVar

Other links and lift over

dbSNP: rs886039548; hg19: chr17-29483145; COSMIC: COSV62206992; COSMIC: COSV62206992;