17-31181787-T-C

Variant names:

• chr17-31181787-T-C
• rs200962248
• NM_001042492.3:c.730+2T>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001042492.3(NF1):​c.730+2T>C variant causes a splice donor, intron change. 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 Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NF1 NM_001042492.3 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.50
• 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: Pathogenic. The variant received 12 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 17-31181787-T-C is Pathogenic according to our data. Variant chr17-31181787-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 1801696.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-31181787-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 1801696.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-31181787-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 1801696.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-31181787-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 1801696.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-31181787-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 1801696.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-31181787-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 1801696.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-31181787-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 1801696.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-31181787-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 1801696.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-31181787-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 1801696.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-31181787-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 1801696.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-31181787-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 1801696.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-31181787-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 1801696.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.730+2T>C		splice_donor_variant, intron_variant	Intron 7 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.730+2T>C		splice_donor_variant, intron_variant	Intron 7 of 56		NP_000258.1
NF1	NM_001128147.3	c.730+2T>C		splice_donor_variant, intron_variant	Intron 7 of 14		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.730+2T>C		splice_donor_variant, intron_variant	Intron 7 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1430606 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 712482

African (AFR) AF: 0.00 AC: 0 AN: 32960

American (AMR) AF: 0.00 AC: 0 AN: 43164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25766

East Asian (EAS) AF: 0.00 AC: 0 AN: 38820

South Asian (SAS) AF: 0.00 AC: 0 AN: 84650

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5254

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1089236

Other (OTH) AF: 0.00 AC: 0 AN: 59352

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:1

Apr 05, 2022

Human Genetics Bochum, Ruhr University Bochum

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG criteria used to clasify this variant: PVS1, PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		5.5
GERP RS		5.9
PromoterAI		-0.067	Neutral
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -2

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

Other links and lift over

dbSNP: rs200962248; hg19: chr17-29508805; COSMIC: COSV62214178;