rs1060500363

Positions:

• chr17-31156001-C-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.79C>T​(p.Gln27*) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.43

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 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 721 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-31156001-C-T is Pathogenic according to our data. Variant chr17-31156001-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 404581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.79C>T	p.Gln27*	stop_gained	2/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.79C>T	p.Gln27*	stop_gained	2/57		NP_000258.1
NF1	NM_001128147.3	c.79C>T	p.Gln27*	stop_gained	2/15		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.79C>T	p.Gln27*	stop_gained	2/58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Medical Genetics, University of Parma	Feb 02, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 29, 2023	This premature translational stop signal has been observed in individual(s) with clinical features of neurofibromatosis type 1 (PMID: 29685074). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln27*) 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). ClinVar contains an entry for this variant (Variation ID: 404581). For these reasons, this variant has been classified as Pathogenic. -

Juvenile myelomonocytic leukemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 04, 2022

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2017

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 30, 2021

The p.Q27* pathogenic mutation (also known as c.79C>T), located in coding exon 2 of the NF1 gene, results from a C to T substitution at nucleotide position 79. This changes the amino acid from a glutamine to a stop codon within coding exon 2. This variant has been observed in individuals with clinical features of neurofibromatosis type 1(Rosset C et al. Expert Rev Mol Diagn, 2018 06;18:577-586) (Demir Gündoan B et al. Turk J Med Sci, 2021 Aug). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.97	D
Vest4		0.93, 0.97
GERP RS		5.0
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: rs1060500363; hg19: chr17-29483019;