rs200962248

chr17-31181787-T-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PP3_Strong

The NM_001042492.3(NF1):c.730+2T>G variant causes a splice donor change. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00097 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NF1 NM_001042492.3 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 B:2
• Conservation: PhyloP100: 5.50

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: Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.730+2T>G		splice_donor_variant		ENST00000358273.9
NF1	NM_000267.3	c.730+2T>G		splice_donor_variant
NF1	NM_001128147.3	c.730+2T>G		splice_donor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.730+2T>G		splice_donor_variant		1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 68 AN: 148750 Hom.: 0 Cov.: 31 FAILED QC

Gnomad AFR AF: 0.0000973

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000415

Gnomad ASJ AF: 0.000875

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000429

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000791

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000968 AC: 1382 AN: 1427330 Hom.: 0 Cov.: 31 AF XY: 0.00101 AC XY: 715 AN XY: 710726

Gnomad4 AFR exome AF: 0.00165

Gnomad4 AMR exome AF: 0.00604

Gnomad4 ASJ exome AF: 0.000974

Gnomad4 EAS exome AF: 0.00395

Gnomad4 SAS exome AF: 0.000710

Gnomad4 FIN exome AF: 0.00691

Gnomad4 NFE exome AF: 0.000404

Gnomad4 OTH exome AF: 0.000641

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000477 AC: 71 AN: 148844 Hom.: 0 Cov.: 31 AF XY: 0.000609 AC XY: 44 AN XY: 72258

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000414

Gnomad4 ASJ AF: 0.000875

Gnomad4 EAS AF: 0.000198

Gnomad4 SAS AF: 0.000430

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000806

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0216 AC: 2620

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Benign:1

Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2021	Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Observed in an individual via exome sequencing for cancer-susceptibility syndromes in participants with atherosclerosis phenotypes (Johnston et al., 2012); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22703879) -

Neurofibromatosis, type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 25, 2023

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 41676). Disruption of this splice site has been observed in individuals with NF1-related conditions (PMID: 21354044, 22190595). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects a donor splice site in intron 7 of the NF1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Jun 18, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	29
Dann	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		5.9

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: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs200962248; hg19: chr17-29508805; COSMIC: COSV62196846;