rs878853890

Variant names:

• chr17-31235939-CA-C
• rs878853890
• NM_001042492.3:c.3897delA

Your query was ambiguous. Multiple possible variants found:

• chr17-31235939-CA-C
• chr17-31235939-CA-CAA

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.3897delA​(p.Lys1299AsnfsTer10) 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NF1 NM_001042492.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.91
• Publications: 1 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 17-31235939-CA-C is Pathogenic according to our data. Variant chr17-31235939-CA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 237558.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.3897delA	p.Lys1299AsnfsTer10	frameshift	Exon 29 of 58	NP_001035957.1
	NF1	NM_000267.4		c.3897delA	p.Lys1299AsnfsTer10	frameshift	Exon 29 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.3897delA	p.Lys1299AsnfsTer10	frameshift	Exon 29 of 58	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.3897delA	p.Lys1299AsnfsTer10	frameshift	Exon 29 of 57	ENSP00000348498.3
	NF1	ENST00000579081.6	TSL:1	n.3897delA		non_coding_transcript_exon	Exon 29 of 58	ENSP00000462408.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:2

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. It is a frameshift predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000237558/PMID: 21362601). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Jul 06, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Lys1299Asnfs*10) in the NF1 gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). This variant has been reported in an individual affected with neurofibromatosis type 1 (PMID: 25074460). ClinVar contains an entry for this variant (Variation ID: 237558). This variant is not present in population databases (ExAC no frequency).

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

Mar 30, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3897delA pathogenic mutation, located in coding exon 29 of the NF1 gene, results from a deletion of one nucleotide at nucleotide position 3897, causing a translational frameshift with a predicted alternate stop codon (p.K1299Nfs*10). This mutation was reported in an individual with a diagnosis of neurofibromatosis type 1 (NF1), however clinical details were limited (Pasmant E et al. Eur. J. Hum. Genet., 2015 May;23:596-601). In addition to the clinical data presented in the literature, 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs878853890; hg19: chr17-29562957;