17-31182783-G-T

Variant names:

• chr17-31182783-G-T
• rs2952999
• NM_001042492.3:c.888+118G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001042492.3(NF1):​c.888+118G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.65 in 984,026 control chromosomes in the GnomAD database, including 215,062 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (26643 hom., cov: 33)
  • Exomes 𝑓: 0.67 (188419 hom.)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.755
• Publications: 10 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Orphanet
• 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: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046660304).
• BP6: Variant 17-31182783-G-T is Benign according to our data. Variant chr17-31182783-G-T is described in ClinVar as Benign. ClinVar VariationId is 561466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.698 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	NM_001042492.3	MANE Select	c.888+118G>T		intron	N/A	NP_001035957.1
	NF1	NM_000267.4		c.888+118G>T		intron	N/A	NP_000258.1
	NF1	NM_001128147.3		c.888+118G>T		intron	N/A	NP_001121619.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.888+118G>T		intron	N/A	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.888+118G>T		intron	N/A	ENSP00000348498.3
	NF1	ENST00000431387.8	TSL:1	c.888+118G>T		intron	N/A	ENSP00000412921.4

Frequencies

GnomAD3 genomes AF: 0.566 AC: 85784 AN: 151538 Hom.: 26633 Cov.: 33

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.719

Gnomad AMR AF: 0.563

Gnomad ASJ AF: 0.766

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.617

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.703

Gnomad OTH AF: 0.627

GnomAD4 exome AF: 0.665 AC: 553546 AN: 832366 Hom.: 188419 Cov.: 11 AF XY: 0.666 AC XY: 286535 AN XY: 430210

African (AFR) AF: 0.294 AC: 6074 AN: 20684

American (AMR) AF: 0.521 AC: 17440 AN: 33498

Ashkenazi Jewish (ASJ) AF: 0.772 AC: 16451 AN: 21310

East Asian (EAS) AF: 0.456 AC: 15129 AN: 33178

South Asian (SAS) AF: 0.633 AC: 42271 AN: 66828

European-Finnish (FIN) AF: 0.653 AC: 22863 AN: 35000

Middle Eastern (MID) AF: 0.751 AC: 2239 AN: 2982

European-Non Finnish (NFE) AF: 0.699 AC: 404981 AN: 579394

Other (OTH) AF: 0.661 AC: 26098 AN: 39492

GnomAD4 genome AF: 0.566 AC: 85831 AN: 151660 Hom.: 26643 Cov.: 33 AF XY: 0.562 AC XY: 41620 AN XY: 74098

African (AFR) AF: 0.302 AC: 12502 AN: 41402

American (AMR) AF: 0.563 AC: 8585 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.766 AC: 2651 AN: 3462

East Asian (EAS) AF: 0.471 AC: 2428 AN: 5152

South Asian (SAS) AF: 0.615 AC: 2964 AN: 4818

European-Finnish (FIN) AF: 0.653 AC: 6843 AN: 10478

Middle Eastern (MID) AF: 0.772 AC: 227 AN: 294

European-Non Finnish (NFE) AF: 0.703 AC: 47654 AN: 67776

Other (OTH) AF: 0.627 AC: 1326 AN: 2114

Alfa AF: 0.595 Hom.: 4385

Bravo AF: 0.549

TwinsUK AF: 0.694 AC: 2573

ALSPAC AF: 0.696 AC: 2684

Asia WGS AF: 0.533 AC: 1856 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_noAF	Benign	-0.89
CADD	Benign	14
DANN	Benign	0.69
FATHMM_MKL	Benign	0.0048	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.0047	T
PhyloP100		0.76
GERP RS		-0.90
Mutation Taster		=100/0	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: rs2952999; hg19: chr17-29509801; COSMIC: COSV62206121;