rs754023358

Positions:

• chr17-31261768-C-A
• chr17-31261768-C-G
• chr17-31261768-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001042492.3(NF1):​c.4635C>A​(p.Tyr1545Ter) 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 (★). Synonymous variant affecting the same amino acid position (i.e. Y1545Y) has been classified as Likely benign. 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, single submitter P:1
• Conservation: PhyloP100: 0.768

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 12 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 17-31261768-C-A is Pathogenic according to our data. Variant chr17-31261768-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 428949.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.4635C>A	p.Tyr1545Ter	stop_gained	35/58	ENST00000358273.9
NF1	NM_000267.3	c.4572C>A	p.Tyr1524Ter	stop_gained	34/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.4635C>A	p.Tyr1545Ter	stop_gained	35/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2014

The p.Y1545* pathogenic mutation (also known as c.4635C>A) located in coding exon 35 of the NF1 gene, results from a C to A substitution at nucleotide position 4635. This changes the amino acid from a tyrosine to a stop codon within coding exon 35.<span style="background-color: initial;">This pathogenic alteration was described in two individuals with neurofibromatosis type 1 out of a cohort of 565 affected individuals. (<span style="background-color: initial;">Sabbagh A, et al.Hum. Mutat. 2013 Nov; 34(11):1510-8).<span style="background-color: initial;">Additionally, this pathogenic alteration was described in one individual with neurofibromatosis type 1 out of a cohort of 113 affected individuals. (<span style="background-color: initial;">Garcia-Linares C, et al.Hum. Mutat. 2011 Jan; 32(1):78-90). In addition to the clinical data presented in the literature, s<span style="background-color: initial;">ince 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	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.90	D
MutationTaster	Benign	1.0	A;A
Vest4		0.99
GERP RS		0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

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: rs754023358; hg19: chr17-29588786;