rs1555535032

chr17-31338733-CACTT-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001042492.3(NF1):c.6852_6855del(p.Tyr2285ThrfsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,962 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NF1 NM_001042492.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 8.62

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-31338733-CACTT-C is Pathogenic according to our data. Variant chr17-31338733-CACTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 216866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31338733-CACTT-C is described in Lovd as [Pathogenic]. Variant chr17-31338733-CACTT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.6852_6855del	p.Tyr2285ThrfsTer5	frameshift_variant	46/58	ENST00000358273.9
NF1	NM_000267.3	c.6789_6792del	p.Tyr2264ThrfsTer5	frameshift_variant	45/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.6852_6855del	p.Tyr2285ThrfsTer5	frameshift_variant	46/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152128 Hom.: 0 Cov.: 32 FAILED QC

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460962 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 726830

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74306

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

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

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:7

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	Medical Genetics, University of Parma	Dec 20, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Aug 07, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change creates a premature translational stop signal (p.Tyr2264Thrfs*5) in the NF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 and with neurofibromatosis-Noonan syndrome (PMID: 7607663, 16835897, 24357598, 25325900). This variant is also known as c.6850_6853delACTT. ClinVar contains an entry for this variant (Variation ID: 216866). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Feb 05, 2020	- -
Pathogenic, criteria provided, single submitter	research	Department of Research and Development, Institute Hermes Pardini	Feb 02, 2016	PVS1 - disrupt gene (frameshift), PM2 - Absent in population databases, PM4 - Protein lenght change, PP3 - Multiple deleterious effect and PP4 - Patient's phenotype -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 22, 2022	This variant alters the translational reading frame of the NF1 mRNA and causes the premature termination of NF1 protein synthesis. In addition, this variant has been reported in individuals affected with neurofibromatosis and in a family with neurofibromatosis-Noonan syndrome in the published literature (PMIDs: 19738042 (2009), 7607663 (1995), 16835897 (2006), 25325900 (2014), 27980226 (2017) and 24357598 (2014)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2022	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24357598, 30530636, 31371350, 16835897, 7607663, 16944272, 19738042, 27980226, 25325900, 31776437, 34427956) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 22, 2022	This variant is expected to result in the loss of a functional protein. This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features of NF1, including at least one apparent de novo. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 03, 2019

The NF1 c.6852_6855delTTAC; p.Tyr2285fs variant (rs863224836), also known as c.6789_6792delTTAC for NM_000267.3, is reported in the literature in multiple individuals and families affected with neurofibromatosis type 1 (Banerjee 2017, Brems 2009, Griffiths 2007, Lee 2006, Robinson 1995), and a family affected with neurofibromatosis-Noonan syndrome (Ekvall 2014). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 216866), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting 4 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Banerjee S et al. Novel phenotypes of NF1 patients from unrelated Chinese families with tibial pseudarthrosis and anemia. Oncotarget. 2017 Jun 13;8(24):39695-39702. Brems H et al. Glomus tumors in neurofibromatosis type 1: genetic, functional, and clinical evidence of a novel association. Cancer Res. 2009 Sep 15;69(18):7393-401. Ekvall S et al. Novel association of neurofibromatosis type 1-causing mutations in families with neurofibromatosis-Noonan syndrome. Am J Med Genet A. 2014 Mar;164A(3):579-87. Griffiths S et al. Molecular diagnosis of neurofibromatosis type 1: 2 years experience. Fam Cancer. 2007;6(1):21-34. Lee MJ et al. Identification of forty-five novel and twenty-three known NF1 mutations in Chinese patients with neurofibromatosis type 1. Hum Mutat. 2006 Aug;27(8):832. Robinson PN et al. Two recurrent nonsense mutations and a 4 bp deletion in a quasi-symmetric element in exon 37 of the NF1 gene. Hum Genet. 1995 Jul;96(1):95-8. -

Ganglioglioma Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Genome Sciences Centre, British Columbia Cancer Agency

May 21, 2019

- -

Juvenile myelomonocytic leukemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 03, 2023

- -

Neurofibromatosis-Noonan syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

Oct 02, 2021

Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). It is not observed in the gnomAD v2.1.1 dataset (PM2). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 06, 2016

Thec.6852_6855delTTACpathogenic mutation (also known as c.6789_6792delTTACand6789del-TTAC), located in codingexon46 of theNF1gene, results from a deletion of 4 nucleotides from positions 6852 to6855, causing a translationalframeshiftwith a predicted alternate stopcodon(p.Y2285Tfs*5). This pathogenic mutation has beenreported in severalindividuals whofulfilledNIH diagnostic criteria for NF1 (Robinson PN et al.HumGenet.1995;96(1):95-8, Griffiths S, et al.Fam. Cancer 2007 ; 6(1):21-34).In addition to the clinical data presented in the literature, sinceframeshiftsare typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMGRecommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007.Genet Med.2008;10:294). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1555535032; hg19: chr17-29665751;