17-31206278-T-G

Variant names:

• chr17-31206278-T-G
• rs876660099
• NM_001042492.3:c.1299T>G

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.1299T>G​(p.Tyr433*) variant causes a stop gained change involving the alteration of a non-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: 32)
• Consequence: NF1 NM_001042492.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.48

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 17-31206278-T-G is Pathogenic according to our data. Variant chr17-31206278-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 404617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31206278-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.1299T>G	p.Tyr433*	stop_gained	Exon 12 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.1299T>G	p.Tyr433*	stop_gained	Exon 12 of 57		NP_000258.1
NF1	NM_001128147.3	c.1299T>G	p.Tyr433*	stop_gained	Exon 12 of 15		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.1299T>G	p.Tyr433*	stop_gained	Exon 12 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:2

Dec 15, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

While this particular variant has not been reported in the literature, loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). This sequence change creates a premature translational stop signal at codon 433 (p.Tyr433*) of 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. A different variant c.1299T>A (p.Tyr433*) which results in the same protein effect as the one observed here, has been reported in an individual with features of neurofibromatosis type 1 (PMID: 16306205). -

Mar 15, 2022

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Oct 25, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Y433X nonsense variant in the NF1 gene is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Y433X variant is not observed in large population cohorts (Lek et al., 2016). The c.1299T>G variant has not been previously reported to our knowledge, however, c.1299T>A, resulting in the same protein effect (Y433X), has been reported in an individual with features of neurofibromatosis type 1 (Wimmer et al., 2005). In summary, the presence of this variant is consistent with the diagnosis of neurofibromatosis type 1. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.91	D
Vest4		0.98, 0.98, 0.99
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs876660099; hg19: chr17-29533296;