rs267606607

Positions:

• chr17-31259068-AAAG-A

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.4375_4377del​(p.Glu1459del) variant causes a 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K1457K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.30

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 hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain 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 17-31259068-AAAG-A is Pathogenic according to our data. Variant chr17-31259068-AAAG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31259068-AAAG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.4375_4377del	p.Glu1459del	inframe_deletion	33/58	ENST00000358273.9
NF1	NM_000267.3	c.4312_4314del	p.Glu1438del	inframe_deletion	32/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.4375_4377del	p.Glu1459del	inframe_deletion	33/58	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/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
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	Invitae	Jul 08, 2023	This variant, c.4312_4314del, results in the deletion of 1 amino acid(s) of the NF1 protein (p.Glu1438del), 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 individual(s) with classic neurofibromatosis type 1 and neurofibromatosis-Noonan syndrome (NFNS) (PMID: 12707950, 15060124, 18546366, 19863548). In at least one individual the variant was observed to be de novo. This variant is also known as 4312 del GAAdE1438. ClinVar contains an entry for this variant (Variation ID: 364). For these reasons, this variant has been classified as Pathogenic. -

NF1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 10, 2022

The NF1 c.4375_4377delGAA variant is predicted to result in an in-frame deletion (p.Glu1459del). This variant is also described as c.4312_4314delGAA, and has been reported to be causative for neurofibromatosis (Mattocks et al. 2004. PubMed ID: 15060124; Bacci et al. 2010. PubMed ID: 19863548) and has also been reported in a patient with Neurofibromatosis-Noonan syndrome (NFNS) (Baralle et al. 2003. PubMed ID: 12707950). To our knowledge, this variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/364/). Based on this evidence, we interpret this variant as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 24, 2023

In-frame deletion of one amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; Observed in multiple unrelated patients with suspected or clinically diagnosed neurofibromatosis type 1 or NF1-Noonan syndrome referred for genetic testing at GeneDx and in published literature (Baralle et al., 2003; Mattocks et al., 2004; De Luca et al., 2005; Pros et al., 2008; Xu et al., 2014; Kang et al., 2020); Identified as a de novo variant with confirmed parentage in an individual referred for genetic testing at GeneDx and as apparently de novo in an individual in the published literature, both with personal histories consistent with pathogenic variants in this gene (Bacci et al., 2010); This variant is associated with the following publications: (PMID: 15060124, 12707950, 16380919, 18546366, 24789688, 31487937, 23047742, 19863548, 23913538, 31776437, 12807981) -

Neurofibromatosis-Noonan syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 15, 2003

- -

Juvenile myelomonocytic leukemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 01, 2022

- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 13, 2023

The c.4312_4314delGAA variant (also known as p.E1438del) is located in coding exon 32 of the NF1 gene. This variant results from an in-frame GAA deletion at nucleotide positions 4312 to 4314. This results in the in-frame deletion of a glutamic acid at codon 1438. This alteration has been detected in individuals meeting diagnostic criteria for neurofibromatosis type 1 (NF1) (Mattocks C et al. J Med Genet, 2004 Apr;41:e48; Pros E et al. Hum Mutat, 2008 Sep;29:E173-93; Ambry internal data) and in several individuals with clinically definite or suspected NF1 diagnoses (Xu W et al. Int. J. Mol. Med., 2014 Jul;34:53-60; Baralle D et al. Am. J. Med. Genet. A, 2003 May;119A:1-8; Ars E et al. J. Med. Genet., 2003 Jun;40:e82; Sabbagh A et al. Hum Mutat, 2013 Nov;34:1510-8; Kang E et al. J Hum Genet, 2020 Jan;65:79-89). This alteration was reported as a de novo occurrence in an individual with multiple spinal ganglioneuromas and cafe-au-lait spots but who did not have other NF1 features (Bacci C et al. Clin. Genet., 2010 Mar;77:293-7). Of note, this variant is also designated as 4312delGAA and ΔE1438 in published literature. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). As such, this alteration is classified as likely pathogenic. -

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: rs267606607; hg19: chr17-29586086;