17-31334864-G-T

Variant names:

• chr17-31334864-G-T
• rs587782088
• NM_001042492.3:c.5839G>T

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.5839G>T​(p.Glu1947*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 29)
• Consequence: NF1 NM_001042492.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.39
• Publications: 7 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 17-31334864-G-T is Pathogenic according to our data. Variant chr17-31334864-G-T is described in CliVar as Pathogenic. Clinvar id is 141892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31334864-G-T is described in CliVar as Pathogenic. Clinvar id is 141892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31334864-G-T is described in CliVar as Pathogenic. Clinvar id is 141892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31334864-G-T is described in CliVar as Pathogenic. Clinvar id is 141892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31334864-G-T is described in CliVar as Pathogenic. Clinvar id is 141892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31334864-G-T is described in CliVar as Pathogenic. Clinvar id is 141892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31334864-G-T is described in CliVar as Pathogenic. Clinvar id is 141892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31334864-G-T is described in CliVar as Pathogenic. Clinvar id is 141892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31334864-G-T is described in CliVar as Pathogenic. Clinvar id is 141892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31334864-G-T is described in CliVar as Pathogenic. Clinvar id is 141892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.5839G>T	p.Glu1947*	stop_gained	Exon 40 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.5776G>T	p.Glu1926*	stop_gained	Exon 39 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.5839G>T	p.Glu1947*	stop_gained	Exon 40 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:2

Mar 15, 2022

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 25, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 141892). This premature translational stop signal has been observed in individual(s) with NF1-related conditions (PMID: 21520333). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu1926*) in the NF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). -

not provided Pathogenic:1

Aug 28, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29617658, 28152038) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Feb 18, 2014

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

​The p.E1947* pathogenic mutation (also known as c.5839G>T), located in coding exon 40 of the NF1 gene, results from a G to T substitution at nucleotide position 5839. This changes the amino acid from a glutamic acid to a stop codon within coding exon 40. Since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	45
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.4
Vest4		1.0
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs587782088; hg19: chr17-29661882; COSMIC: COSV62206987; COSMIC: COSV62206987;