17-31334984-C-T

Variant names:

• chr17-31334984-C-T
• rs876659070
• NM_001042492.3:c.5959C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001042492.3(NF1):​c.5959C>T​(p.Gln1987*) 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:5
• Conservation: PhyloP100: 7.41

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 17-31334984-C-T is Pathogenic according to our data. Variant chr17-31334984-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 620128.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.5959C>T	p.Gln1987*	stop_gained	Exon 40 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.5896C>T	p.Gln1966*	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.5959C>T	p.Gln1987*	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

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

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

- -

Dec 19, 2019

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. Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). This variant has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10862084). ClinVar contains an entry for this variant (Variation ID: 620128). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln1966*) in the NF1 gene. It is expected to result in an absent or disrupted protein product. -

NF1-related disorder Pathogenic:1

Mar 19, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NF1 c.5959C>T variant is predicted to result in premature protein termination (p.Gln1987*). This variant, described as c.5896C>T p.Q1966X, was reported in an individual with neurofibromatosis type 1 (Messiaen et al. 2000. PubMed ID: 10862084). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant is interpreted as pathogenic (https://preview.ncbi.nlm.nih.gov/clinvar/variation/620128/). Nonsense variants in NF1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Sep 28, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Q1966X nonsense variant in the NF1 gene has been reported previously in association with neurofibromatosis type 1 (Messiaen et al., 2000). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant is not observed in large population cohorts (Lek et al., 2016). We classify this variant as pathogenic. -

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

Aug 06, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q1966* pathogenic mutation (also known as c.5896C>T), located in coding exon 39 of the NF1 gene, results from a C to T substitution at nucleotide position 5896. This changes the amino acid from a glutamine to a stop codon within coding exon 39. This variant, also reported as p.Q1966X, has been observed in at least one individual with a personal and family history that is consistent with Neurofibromatosis type 1 (Ambry internal data; Messiaen LM et al. Hum Mutat, 2000;15:541-55). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.97	D
Vest4		0.97
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs876659070; hg19: chr17-29662002; COSMIC: COSV62196029; COSMIC: COSV62196029;