17-31338024-G-T

Variant names:

• chr17-31338024-G-T
• rs1060500356
• NM_001042492.3:c.6705-1G>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.6705-1G>T variant causes a splice acceptor, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.23

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: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-31338024-G-T is Pathogenic according to our data. Variant chr17-31338024-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 836704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31338024-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.6705-1G>T		splice_acceptor_variant, intron_variant	Intron 44 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.6642-1G>T		splice_acceptor_variant, intron_variant	Intron 43 of 56		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.6705-1G>T		splice_acceptor_variant, intron_variant	Intron 44 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6705-1G>T splice acceptor variant in NF1 gene has been reported in individual(s) with neurofibromatosis type 1 (Fahsold et al., 2000). The c.6705-1G>T variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. Loss-of-function variants in NF1 are known to be pathogenic (Fahsold et al., 2000; Sabbagh et al., 2013). For these reasons, this variant has been classified as Pathogenic -

Dec 26, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10712197, Invitae). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 43 of the NF1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.23	D
ClinPred		0.99	D
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.82		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.82		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060500356; hg19: chr17-29665042; COSMIC: COSV62198415; COSMIC: COSV62198415;