chr17-31167675-C-G

Variant names:

• chr17-31167675-C-G
• rs2953016
• NM_001042492.3:c.480-2216C>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.480-2216C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.6 in 152,032 control chromosomes in the GnomAD database, including 31,359 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 0.60 (31359 hom., cov: 32)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.271
• 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.776 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042492.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	NM_001042492.3	MANE Select	c.480-2216C>G		intron	N/A	NP_001035957.1
	NF1	NM_000267.4		c.480-2216C>G		intron	N/A	NP_000258.1
	NF1	NM_001128147.3		c.480-2216C>G		intron	N/A	NP_001121619.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.480-2216C>G		intron	N/A	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.480-2216C>G		intron	N/A	ENSP00000348498.3
	NF1	ENST00000431387.8	TSL:1	c.480-2216C>G		intron	N/A	ENSP00000412921.4

Frequencies

GnomAD3 genomes AF: 0.600 AC: 91142 AN: 151914 Hom.: 31358 Cov.: 32

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.763

Gnomad AMR AF: 0.582

Gnomad ASJ AF: 0.808

Gnomad EAS AF: 0.563

Gnomad SAS AF: 0.642

Gnomad FIN AF: 0.728

Gnomad MID AF: 0.782

Gnomad NFE AF: 0.782

Gnomad OTH AF: 0.650

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

GnomAD4 genome AF: 0.600 AC: 91166 AN: 152032 Hom.: 31359 Cov.: 32 AF XY: 0.597 AC XY: 44336 AN XY: 74316

African (AFR) AF: 0.250 AC: 10383 AN: 41460

American (AMR) AF: 0.581 AC: 8884 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.808 AC: 2807 AN: 3472

East Asian (EAS) AF: 0.562 AC: 2902 AN: 5168

South Asian (SAS) AF: 0.641 AC: 3091 AN: 4822

European-Finnish (FIN) AF: 0.728 AC: 7684 AN: 10554

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.782 AC: 53119 AN: 67960

Other (OTH) AF: 0.651 AC: 1373 AN: 2110

Alfa AF: 0.548 Hom.: 1843

Bravo AF: 0.577

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.8
DANN	Benign	0.56
PhyloP100		0.27
Mutation Taster		=99/1	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: rs2953016; hg19: chr17-29494693;