NM_001042492.3:c.2970_2972delAAT

Variant names:

• chr17-31229953-CAAT-C
• rs267606606
• NM_001042492.3:c.2970_2972delAAT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PM1 PM2 PM4_Supporting PP5_Very_Strong BS2_Supporting

The NM_001042492.3(NF1):​c.2970_2972delAAT​(p.Met991del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,504 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: NF1 NM_001042492.3 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:27 O:1
• Conservation: PhyloP100: 8.91
• Publications: 44 publications found

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 Gene-Disease associations (from GenCC):

• neurofibromatosis type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
• Moyamoya disease

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 27 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 17-31229953-CAAT-C is Pathogenic according to our data. Variant chr17-31229953-CAAT-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.2970_2972delAAT	p.Met991del	disruptive_inframe_deletion	Exon 22 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.2970_2972delAAT	p.Met991del	disruptive_inframe_deletion	Exon 22 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.2970_2972delAAT	p.Met991del	disruptive_inframe_deletion	Exon 22 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250346 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1459504 Hom.: 0 AF XY: 0.00000413 AC XY: 3 AN XY: 726064

African (AFR) AF: 0.00 AC: 0 AN: 33396

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86162

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111690

Other (OTH) AF: 0.0000166 AC: 1 AN: 60194

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:27 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:13 Other:1

Mar 15, 2022

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.2970_2972del, results in the deletion of 1 amino acid(s) of the NF1 protein (p.Met992del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs267606606, gnomAD no frequency). This variant has been observed in individual(s) with clinical features of NF1-related conditions (PMID: 7904209, 12807981, 17160901, 20602485, 21532985, 23047742). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 363). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -

Oct 22, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Inframe deletion located in a nonrepeat region: predicted to change the length of the protein and disrupt normal protein function. The variant has been previously reported as de novo in a similarly affected individual (PMID: 30190611). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 23656349, 30190611, 30308447). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000000363 /PMID: 7904209 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

May 08, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PM2, PM4, PM6_Strong, PP1_Strong -

Dec 20, 2019

Medical Genetics, University of Parma

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Dec 30, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 10, 2022

Institute of Medical Genetics, University of Zurich

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Nov 09, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 21, 2025

Department of Human Genetics, Hannover Medical School

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG: PS3_Supporting, PM4, PP1_Strong -

Feb 24, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NF1 c.2970_2972delAAT (p.Met992del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 4e-06 in 250346 control chromosomes. c.2970_2972delAAT has been reported in the literature in a large number of individuals affected with NF1 Related Conditions (e.g. Stevenson_2006, Tsipi_2018, Koczkowska_2019). These data indicate that the variant is very likely to be associated with disease. A study on 135 individuals carrying this variant showed that these individuals have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas (Koczkowska_2019). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Feb 26, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 15, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Met992del variant in NF1 has been previously reported in >20 individuals w ith NF1, segregated with disease in >20 affected relatives, and was de novo in a t least 1 of these individuals (Upadhyaya 2007, Quintans 2011). Individuals with this variant were reported to not have cutaneous neurofibromas (Upadhyaya 2007, Quintans 2011). This variant has also been reported in ClinVar (Variation ID: 3 63) and has been identified in 1/66338 European chromosomes by the Exome Aggrega tion Consortium (ExAC, http://exac.broadinstitute.org). This variant is a deleti on of 1 amino acid at position 992 and is not predicted to alter the protein rea ding frame. In summary, this variant meets our criteria to be classified as path ogenic for NF1 in an autosomal dominant manner based upon frequency in probands and segregation studies. -

not provided Pathogenic:8

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 23, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PM2, PM6, PS4_moderate -

Jan 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; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26740943, 26056819, 25329635, 26345759, 12807981, 25074460, 26962827, 27920686, 28213670, 27785414, 27322453, 10712197, 10862084, 7904209, 14569132, 16380919, 16542390, 20602485, 23047742, 26457592, 25966637, 16944272, 18546366, 23656349, 25370043, 23972508, 17160901, 26178382, 24232412, 26979265, 26956402, 27838393, 30190611, 30109123, 1568246, 29968256, 31717729, 31776437, 21532985, 31370276, 32107864, 25486365, 2121369) -

Jun 27, 2024

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Many individuals with this variant are reported to present with a milder phenotype (PMID: 17160901, 20602485, 30190611, 34897289). This variant appears to segregate with disease in at least one family. -

Nov 22, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NF1 c.2970_2972del; p.Met992del variant (rs267606606) is reported in the literature in several unrelated individuals and families affected with a milder form of neurofibromatosis type 1 (NF1), characterized by a lack of neurofibromas (Kehrer-Sawatzki 2015, Koczkowska 2019, Quintans 2011, Upadhyaya 2007). This variant is also reported in ClinVar (Variation ID: 363). This variant is only observed on one allele in 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. Based on available information, this variant is considered to be pathogenic. References: Kehrer-Sawatzki H et al. Neurofibromatosis Type 1 Without Neurofibromas: Genotype-Phenotype Correlations in NF1. Hum Mutat. 2015 Nov;36(11):v. PMID: 26457592. Koczkowska M et al. Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation. Genet Med. 2019 Apr;21(4):867-876. PMID: 30190611. Quintans B et al. Neurofibromatosis without Neurofibromas: Confirmation of a Genotype-Phenotype Correlation and Implications for Genetic Testing. Case Rep Neurol. 2011 Apr 11;3(1):86-90. PMID: 21532985. Upadhyaya M et al. An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation. Am J Hum Genet. 2007 Jan;80(1):140-51. PMID: 17160901. -

Jan 16, 2018

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurofibromatosis, type 1;C0349639:Juvenile myelomonocytic leukemia;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome Pathogenic:1

Sep 28, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurofibromatosis-Noonan syndrome Pathogenic:1

Jan 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Gastric cancer Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Juvenile myelomonocytic leukemia Pathogenic:1

Sep 26, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Café-au-lait macules with pulmonary stenosis Pathogenic:1

Jan 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jan 19, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

​The c.2970_2972delAAT pathogenic mutation (also known as p.M992del and delM992) is located in coding exon 22 of the NF1 gene. This alteration results from an in-frame AAT deletion between nucleotide positions 2970 and 2972. This results in the deletion of a highly conserved methionine residue at codon992. This alteration was first identified in two unrelated probands with paternally inherited neurofibromatosis type 1 (NF1) (Shen MH et al. Hum Mol Genet. 1993; 2(11):1861-4). Later studies suggest this mutation is associated with an attenuated form of NF1 similar to Legious syndrome; individuals with this mutation are not likely to develop neurofibromas (Upadhyaya M et al. Am J Hum Genet. 2007; 80(1):140-51). Based on the supporting evidence, c.2970_2972delAAT is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9
Mutation Taster		=12/88	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs267606606; hg19: chr17-29556971;