Variant rs864622639 details in Genebe, Genetics Data Aggregator

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:15

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/exons	MANE	Protein	UniProt
NF1	NM_001042492.3 link	c.7159_7164delAACTTT	p.Asn2387_Phe2388del	conservative_inframe_deletion	48/58	ENST00000358273.9	NP_001035957.1	P21359-1
NF1	NM_000267.3 link	c.7096_7101delAACTTT	p.Asn2366_Phe2367del	conservative_inframe_deletion	47/57		NP_000258.1	P21359-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 link	c.7159_7164delAACTTT	p.Asn2387_Phe2388del	conservative_inframe_deletion	48/58	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:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurofibromatosis, type 1

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 05, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Mar 09, 2023	- -
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	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PM4+PS4+PM6_Supporting+PP1+PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Medical Genetics, University of Parma	Dec 20, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -

not provided

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	May 28, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 17, 2022	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. -

Neurofibromatosis, type 1;C4024216:Tibial pseudarthrosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

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

Nov 10, 2018

- -

NF1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 30, 2023

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

Pathogenic, no assertion criteria provided

provider interpretation

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Sep 01, 2020

- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2024

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

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