chr17-31233143-CAAT-C

Variant names:

• chr17-31233143-CAAT-C
• rs1060500276
• NM_001042492.3:c.3639_3641delAAT

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_001042492.3(NF1):​c.3639_3641delAAT​(p.Met1214del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 8.91

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 13 ACMG points.

• PM1: In a helix (size 8) in uniprot entity NF1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_001042492.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001042492.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 17-31233143-CAAT-C is Pathogenic according to our data. Variant chr17-31233143-CAAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 404465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31233143-CAAT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.3639_3641delAAT	p.Met1214del	disruptive_inframe_deletion	Exon 27 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.3639_3641delAAT	p.Met1214del	disruptive_inframe_deletion	Exon 27 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.3639_3641delAAT	p.Met1214del	disruptive_inframe_deletion	Exon 27 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:4

Aug 17, 2022

Medical Genetics, University of Parma

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 26, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.3639_3641del, results in the deletion of 1 amino acid(s) of the NF1 protein (p.Met1215del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with neurofibromatosis type 1 (PMID: 10712197, 16835897, 18546366, 26635368). This variant is also known as 3643delATG. ClinVar contains an entry for this variant (Variation ID: 404465). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects NF1 function (PMID: 26635368). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

May 05, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame deletion of 1 amino acid in a non-repeat region; Observed in individuals with Neurofibromatosis type 1 (Lee 2006, Pros 2008, Cannon 2018, Hirata 2016); In silico analysis supports a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10712197, 16835897, 26635368, 29415745, 18546366, 25486365, 22807134) -

Aug 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NF1 c.3639_3641del; p.Met1215del variant (rs1060500276; ClinVar ID: 404465) is reported in the literature in multiple individuals with a diagnosis or suspicion of neurofibromatosis type 1 (Cannon 2018, Fahsold 2000, Flores Pimentel 2022, Lee 2006, Martorana 2023, Pros 2008, Sabbagh 2013). This variant is also absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant deletes a single methionine residue leaving the rest of the protein in-frame. Functional studies demonstrate that this variant disrupts interactions with the NF1 binding partner protein SPRED1 (Dunzendorfer-Matt 2016, Hirata 2016). Based on available information, this variant is considered to be pathogenic. References: Cannon A et al. Cutaneous neurofibromas in Neurofibromatosis type I: a quantitative natural history study. Orphanet J Rare Dis. 2018 Feb 7;13(1):31. PMID: 29415745. Dunzendorfer-Matt T et al. The neurofibromin recruitment factor Spred1 binds to the GAP related domain without affecting Ras inactivation. Proc Natl Acad Sci U S A. 2016 Jul 5;113(27):7497-502. PMID: 27313208. Fahsold R et al. Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. Am J Hum Genet. 2000 Mar;66(3):790-818. PMID: 10712197. Flores Pimentel M et al. Prevalence of Choroidal Abnormalities and Lisch Nodules in Children Meeting Clinical and Molecular Diagnosis of Neurofibromatosis Type 1. Transl Vis Sci Technol. 2022 Feb 1;11(2):10. PMID: 35119474. Hirata Y et al. Interaction between a Domain of the Negative Regulator of the Ras-ERK Pathway, SPRED1 Protein, and the GTPase-activating Protein-related Domain of Neurofibromin Is Implicated in Legius Syndrome and Neurofibromatosis Type 1. J Biol Chem. 2016 Feb 12;291(7):3124-34. PMID: 26635368. 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. PMID: 16835897. Martorana D et al. Reassessment of the NF1 variants of unknown significance found during the 20-year activity of a genetics diagnostic laboratory. Eur J Med Genet. 2023 Nov;66(11):104847. PMID: 37751797. 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. PMID: 18546366. Sabbagh A et al. NF1 molecular characterization and neurofibromatosis type I genotype-phenotype correlation: the French experience. Hum Mutat. 2013 Nov;34(11):1510-8. PMID: 23913538. -

Neurofibromatosis-Noonan syndrome Pathogenic:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense variant c.3639_3641del(p.Met1215del) in NF1 gene has been reported previously in heterozygous state in multiple individuals with neurofibromatosis type 1 (Cannon A, et al., 2018, Dunzendorfer-Matt T, et al., 2016). Experimental studies have demonstrated that this alteration impairs binding to the EVH1 domain of SPRED1, which functions as a negative regulator of the Ras-ERK pathway and interacts with neurofibromin, the NF1 gene product (Hirata Y, et al., 2016). The c.3639_3641del (p.Met1215del) variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submitters). This p.Met1215del causes deletion of amino acid Methionine at position 1215. For these reasons, this variant has been classified as Pathogenic. -

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

Jun 02, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3639_3641delAAT pathogenic mutation (also known as p.M1215del) is located in coding exon 27 of the NF1 gene. This pathogenic mutation results from an in-frame AAT deletion at nucleotide positions 3639 to 3641. This results in the in-frame deletion of a methionine at codon 1215. This alteration has been reported in several individuals affected with neurofibromatosis type 1 (Fahsold R et al. Am J Hum Genet, 2000 Mar;66:790-818; Lee MJ et al. Hum Mutat, 2006 Aug;27:832; Pros E et al. Hum Mutat, 2008 Sep;29:E173-93; Sabbagh A et al. Hum Mutat, 2013 Nov;34:1510-8; Hirata Y et al. J Biol Chem, 2016 Feb;291:3124-34). Functional studies have also demonstrated that this alteration impairs binding to the EVH1 domain of SPRED1 (Hirata Y et al. J Biol Chem, 2016 Feb;291:3124-34; Dunzendorfer-Matt T et al. Proc Natl Acad Sci U S A, 2016 07;113:7497-502). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1060500276; hg19: chr17-29560161;