rs1060500276

chr17-31233143-CAAT-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM4_Supporting PP5_Very_Strong

The NM_001042492.3(NF1):c.3639_3641del(p.Met1215del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T1213T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• 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 11 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_001042492.3
• 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/exons	MANE	UniProt
NF1	NM_001042492.3	c.3639_3641del	p.Met1215del	inframe_deletion	27/58	ENST00000358273.9
NF1	NM_000267.3	c.3639_3641del	p.Met1215del	inframe_deletion	27/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.3639_3641del	p.Met1215del	inframe_deletion	27/58	1	NM_001042492.3	P1

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	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 protein 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. -
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	- -
Pathogenic, criteria provided, single submitter	clinical testing	Medical Genetics, University of Parma	Aug 17, 2022	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 05, 2022

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) -

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2021

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;