NM_001042492.3:c.7330_7331insAA

Variant names:

• chr17-31350190-T-TAA
• rs1064794278
• NM_001042492.3:c.7330_7331insAA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001042492.3(NF1):​c.7330_7331insAA​(p.Thr2444LysfsTer13) variant causes a frameshift 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T2444T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.44
• Publications: 6 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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-31350190-T-TAA is Pathogenic according to our data. Variant chr17-31350190-T-TAA is described in ClinVar as Pathogenic. ClinVar VariationId is 504361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042492.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	NM_001042492.3	MANE Select	c.7330_7331insAA	p.Thr2444LysfsTer13	frameshift	Exon 50 of 58	NP_001035957.1
	NF1	NM_000267.4		c.7267_7268insAA	p.Thr2423LysfsTer13	frameshift	Exon 49 of 57	NP_000258.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.7330_7331insAA	p.Thr2444LysfsTer13	frameshift	Exon 50 of 58	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.7267_7268insAA	p.Thr2423LysfsTer13	frameshift	Exon 49 of 57	ENSP00000348498.3
	NF1	ENST00000579081.6	TSL:1	n.*2495_*2496insAA		non_coding_transcript_exon	Exon 50 of 58	ENSP00000462408.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Feb 16, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7267_7268insAA variant in the NF1 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This insertion causes a frameshift starting with codon Threonine 2423, changes this amino acid to a Lysine residue and creates a premature Stop codon at position 13 of the new reading frame, denoted p.Thr2423LysfsX13. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.7267_7268insAA variant is not observed in large population cohorts (Lek et al., 2016). Based on currently available evidence, we consider this a pathogenic variant.

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

Jan 02, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7267_7268insAA pathogenic mutation, located in coding exon 49 of the NF1 gene, results from an insertion of two nucleotides at position 7267, causing a translational frameshift with a predicted alternate stop codon (p.T2423Kfs*13). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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

Molecular Genetics Department, Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A previously undescribed heterozygous nucleotide variant creates a frameshift p.Thr2444LysfsTer13 in the NF1 gene (rs1064794278). Heterozygous loss-of-function variants are reported in patients with neurofibromatosis, familial spinal, 162210; Neurofibromatosis-Noonan syndrome, 601321; Neurofibromatosis, type 1, 162200; Watson syndrome, 193520. The variant is not present in population database (gnomAD no frequency). Another heterozygous variant leading to a frameshift and resulting in loss of the full-length protein, has been reported in patients with neurofibromatosis [Martínez et al., 2024, PMID: 39596125; Osborne et al., 1999, PMID: 10543400]. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.4
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1064794278; hg19: chr17-29677208;