dbSNP rs864622639: NF1:p.Asn2387_Phe2388del (chr17-31343097-CTAACTT-C) – ACMG Classification: Pathogenic (13 pts)

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PM4PP3PP5_Very_Strong

The NM_001042492.3(NF1):c.7159_7164delAACTTT(p.Asn2387_Phe2388del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,828 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NF1
NM_001042492.3 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 8.56

Variant links:

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]

NF1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_001042492.3.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

PP5

Variant 17-31343097-CTAACTT-C is Pathogenic according to our data. Variant chr17-31343097-CTAACTT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 220715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31343097-CTAACTT-C is described in Lovd as [Pathogenic]. Variant chr17-31343097-CTAACTT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3 link	c.7159_7164delAACTTT	p.Asn2387_Phe2388del	conservative_inframe_deletion	Exon 48 of 58	ENST00000358273.9	NP_001035957.1	P21359-1
NF1	NM_000267.3 link	c.7096_7101delAACTTT	p.Asn2366_Phe2367del	conservative_inframe_deletion	Exon 47 of 57		NP_000258.1	P21359-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 link	c.7159_7164delAACTTT	p.Asn2387_Phe2388del	conservative_inframe_deletion	Exon 48 of 58	1	NM_001042492.3	ENSP00000351015.4		P21359-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461680

Hom.:

AF XY:

0.00

AC XY:

AN XY:

727152

show subpopulations

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74324

show subpopulations

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurofibromatosis, type 1

Pathogenic:7

Mar 09, 2023

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.7096_7101del, results in the deletion of 2 amino acid(s) of the NF1 protein (p.Asn2366_Phe2367del), 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 (PMID: 8081387, 10862084, 18546366, 24789688). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 220715). For these reasons, this variant has been classified as Pathogenic. -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

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

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PM4+PS4+PM6_Supporting+PP1+PP4 -

Dec 20, 2019

Medical Genetics, University of Parma

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 15, 2022

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:5

May 28, 2020

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NF1 c.7159_7164del; p.Asn2387_Phe2388del variant (rs864622639), also known as 7096_7101del, is reported as a common recurrent pathogenic variant in several individuals with NF1 (Abernathy 1994, Ars 2003, Messian 2000, Riva 2022, Xu 2014). This variant is also reported in ClinVar (Variation ID: 220715). It is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant deletes two amino acid residues leaving the rest of the protein in-frame. Based on available information, this variant is considered to be pathogenic. References: Abernathy CR et al. Two NF1 mutations: frameshift in the GAP-related domain, and loss of two codons toward the 3' end of the gene. Hum Mutat. 1994;3(4):347-52. PMID: 8081387. Ars E et al. Recurrent mutations in the NF1 gene are common among neurofibromatosis type 1 patients. J Med Genet. 2003 Jun;40(6):e82. PMID: 12807981. Messiaen LM et al. Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects. Hum Mutat. 2000;15(6):541-55. PMID: 10862084. Riva M et al. Recurrent NF1 gene variants and their genotype/phenotype correlations in patients with Neurofibromatosis type I. Genes Chromosomes Cancer. 2022 Jan;61(1):10-21. PMID: 34427956. Xu W et al. Fifty-four novel mutations in the NF1 gene and integrated analyses of the mutations that modulate splicing. Int J Mol Med. 2014 Jul;34(1):53-60. PMID: 24789688. -

Jun 17, 2022

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been identified in multiple unrelated individuals with clinical features of NF1, including at least one apparent de novo case. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as c.7159_7164del. -

May 11, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame deletion of 2 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.2366delNF; This variant is associated with the following publications: (PMID: 32405727, 25293717, 18546366, 12807981, 25541118, 10862084, 8081387, 30014477, 31766501, 31533797, 31776437, 33372952) -

Dec 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurofibromatosis, type 1;C4024216:Tibial pseudarthrosis

Pathogenic:1

Nov 10, 2018

The Laboratory of Genetics and Metabolism, Hunan Children’s Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

NF1-related disorder

Pathogenic:1

Oct 30, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NF1 c.7159_7164del6 variant is predicted to result in an in-frame deletion (p.Asn2387_Phe2388del). This variant is often reported as c.7096_7101del (p.Asn2366_Phe2367del) in the literature. This variant was reported in individuals with Neurofibromatosis 1 (see examples: Abernathy et al. 1994. PubMed ID: 8081387; Zhu et al. 2019. PubMed ID: 31533797; Riva et al. 2021. PubMed ID: 34427956; Courtney. 2020. PubMed ID: 32405727; Ulusal et al. 2017. PubMed ID: 28924536). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant is interpreted as pathogenic (https://preview.ncbi.nlm.nih.gov/clinvar/variation/220715/). This variant is interpreted as pathogenic. -

Rhabdomyosarcoma

Pathogenic:1

Sep 01, 2020

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Pathogenic:1

Jan 24, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7096_7101delAACTTT (p.N2366_F2367del) alteration, located in coding exon 47 of the NF1 gene, results from an in-frame deletion of 6 nucleotides at positions c.7096 to c.7101. This results in the deletion of 2 amino acids between codons 2366 and 2367. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in in several unrelated individuals with a clinical diagnoses of NF1 and was confirmed as a de novo mutation in one individual with sporadic NF1. This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis (Choi, 2012). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over