chr17-31325997-C-A

Position:

• chr17-31325997-C-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001042492.3(NF1):​c.5013C>A​(p.Tyr1671*) 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 Conflicting classifications of pathogenicity (no stars). 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:2
• Conservation: PhyloP100: -0.253

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 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 17-31325997-C-A is Pathogenic according to our data. Variant chr17-31325997-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 404434.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.5013C>A	p.Tyr1671*	stop_gained	37/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.4950C>A	p.Tyr1650*	stop_gained	36/57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.5013C>A	p.Tyr1671*	stop_gained	37/58	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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 08, 2019	This nonsense change has been observed in several individuals affected with neurofibromatosis, type 1 (PMID: 22155606, 22108604, 15060124, 27999334). ClinVar contains an entry for this variant (Variation ID: 404434). 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 is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr1650*) in the NF1 gene. It is expected to result in an absent or disrupted protein product. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	The stop gained c.5013C>A (p.Tyr1671Ter) variant in the NF1 gene has been been reported as a recurring pathogenic variant in several individuals affected with Neurofibromatosis Type 1 (Thomas, Laura et al., 2012). This variant is absent in the gnomAD. This variant has been reported to the ClinVar database as Pathogenic. Computational evidence (MutationTaster - Disease causing) predicts damaging effect on protein structure and function for this variant. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Benign	0.13
Eigen_PC	Benign	-0.083
FATHMM_MKL	Benign	0.61	D
Vest4		0.93
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060500255; hg19: chr17-29653015;