rs777759972

Positions:

• chr17-31232070-C-A
• chr17-31232070-C-G
• chr17-31232070-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001042492.3(NF1):​c.3198-3C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0032 (0 hom., cov: 0)
  • Exomes 𝑓: 0.090 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NF1 NM_001042492.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.05209
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.140

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.3198-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.3198-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.3198-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001042492.3	ENSP00000351015	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 73 AN: 22768 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.00257

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00344

Gnomad ASJ AF: 0.00151

Gnomad EAS AF: 0.00691

Gnomad SAS AF: 0.00843

Gnomad FIN AF: 0.00659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00280

Gnomad OTH AF: 0.00307

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0905 AC: 11076 AN: 122414 Hom.: 0 Cov.: 3 AF XY: 0.0861 AC XY: 5483 AN XY: 63716

Gnomad4 AFR exome AF: 0.0725

Gnomad4 AMR exome AF: 0.0181

Gnomad4 ASJ exome AF: 0.0410

Gnomad4 EAS exome AF: 0.0250

Gnomad4 SAS exome AF: 0.0368

Gnomad4 FIN exome AF: 0.0134

Gnomad4 NFE exome AF: 0.115

Gnomad4 OTH exome AF: 0.0698

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00321 AC: 73 AN: 22772 Hom.: 0 Cov.: 0 AF XY: 0.00344 AC XY: 37 AN XY: 10752

Gnomad4 AFR AF: 0.00274

Gnomad4 AMR AF: 0.00344

Gnomad4 ASJ AF: 0.00151

Gnomad4 EAS AF: 0.00694

Gnomad4 SAS AF: 0.00855

Gnomad4 FIN AF: 0.00659

Gnomad4 NFE AF: 0.00272

Gnomad4 OTH AF: 0.00307

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurofibromatosis, type 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 18, 2020	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. This variant has not been reported in the literature in individuals with NF1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 24 of the NF1 gene. It does not directly change the encoded amino acid sequence of the NF1 protein, but it affects a nucleotide within the consensus splice site of the intron. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Nov 15, 2021

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2024

NF1: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	12
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.052
dbscSNV1_RF	Benign	0.44
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.26		Position offset: 5

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

Publications

LitVar

Other links and lift over

dbSNP: rs777759972; hg19: chr17-29559088;