NM_001042492.3:c.1392+1G>T

Variant names:

• chr17-31206372-G-T
• rs267604791
• NM_001042492.3:c.1392+1G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001042492.3(NF1):​c.1392+1G>T variant causes a splice donor, 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_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.35
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• neurofibromatosis type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
• Moyamoya disease

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.015492958 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-31206372-G-T is Pathogenic according to our data. Variant chr17-31206372-G-T is described in CliVar as Pathogenic. Clinvar id is 1177439.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-31206372-G-T is described in CliVar as Pathogenic. Clinvar id is 1177439.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-31206372-G-T is described in CliVar as Pathogenic. Clinvar id is 1177439.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-31206372-G-T is described in CliVar as Pathogenic. Clinvar id is 1177439.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-31206372-G-T is described in CliVar as Pathogenic. Clinvar id is 1177439.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-31206372-G-T is described in CliVar as Pathogenic. Clinvar id is 1177439.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-31206372-G-T is described in CliVar as Pathogenic. Clinvar id is 1177439.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-31206372-G-T is described in CliVar as Pathogenic. Clinvar id is 1177439.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-31206372-G-T is described in CliVar as Pathogenic. Clinvar id is 1177439.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-31206372-G-T is described in CliVar as Pathogenic. Clinvar id is 1177439.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-31206372-G-T is described in CliVar as Pathogenic. Clinvar id is 1177439.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-31206372-G-T is described in CliVar as Pathogenic. Clinvar id is 1177439.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.1392+1G>T		splice_donor_variant, intron_variant	Intron 12 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.1392+1G>T		splice_donor_variant, intron_variant	Intron 12 of 56		NP_000258.1
NF1	NM_001128147.3	c.1392+1G>T		splice_donor_variant, intron_variant	Intron 12 of 14		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.1392+1G>T		splice_donor_variant, intron_variant	Intron 12 of 57	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:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Dec 26, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant demonstrated to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease (PMID: 23913538); Identified in patients with neurofibromatosis type 1 (NF1) referred for genetic testing at GeneDx and in published literature (PMID: 23913538, 31776437); Not observed at significant frequency in large population cohorts (gnomAD); Also known as IVS10a+1G>T; This variant is associated with the following publications: (PMID: 23913538, 31776437) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		9.3
GERP RS		6.1
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: -1

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

Other links and lift over

dbSNP: rs267604791; hg19: chr17-29533390; COSMIC: COSV62202943;