17-31233782-A-G

Variant names:

• chr17-31233782-A-G
• rs2012581
• NM_001042492.3:c.3708+569A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001042492.3(NF1):​c.3708+569A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 152,088 control chromosomes in the GnomAD database, including 16,108 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.43 (16108 hom., cov: 32)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.33
• Publications: 7 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.3708+569A>G		intron_variant	Intron 27 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.3708+569A>G		intron_variant	Intron 27 of 56		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.3708+569A>G		intron_variant	Intron 27 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.427 AC: 64961 AN: 151970 Hom.: 16087 Cov.: 32

Gnomad AFR AF: 0.678

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.433

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.537

Gnomad SAS AF: 0.383

Gnomad FIN AF: 0.343

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.296

Gnomad OTH AF: 0.366

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.428 AC: 65030 AN: 152088 Hom.: 16108 Cov.: 32 AF XY: 0.432 AC XY: 32127 AN XY: 74368

African (AFR) AF: 0.678 AC: 28105 AN: 41470

American (AMR) AF: 0.433 AC: 6624 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 812 AN: 3464

East Asian (EAS) AF: 0.537 AC: 2779 AN: 5172

South Asian (SAS) AF: 0.384 AC: 1855 AN: 4828

European-Finnish (FIN) AF: 0.343 AC: 3630 AN: 10570

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.296 AC: 20138 AN: 67982

Other (OTH) AF: 0.365 AC: 771 AN: 2110

Alfa AF: 0.398 Hom.: 1771

Bravo AF: 0.445

Asia WGS AF: 0.469 AC: 1630 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.5
DANN	Benign	0.81
PhyloP100		1.3
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2012581; hg19: chr17-29560800;