rs2285892

Variant names:

• chr17-31226467-G-A
• rs2285892
• NM_001042492.3:c.2034G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-31226467-G-A
• chr17-31226467-G-T
• chr17-31226467-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001042492.3(NF1):​c.2034G>A​(p.Pro678Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.336 in 1,613,246 control chromosomes in the GnomAD database, including 99,275 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P678P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.43 (15875 hom., cov: 31)
  • Exomes 𝑓: 0.33 (83400 hom.)
• Consequence: NF1 NM_001042492.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: -1.28
• Publications: 59 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 17-31226467-G-A is Benign according to our data. Variant chr17-31226467-G-A is described in ClinVar as Benign. ClinVar VariationId is 183826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.28 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.667 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.2034G>A	p.Pro678Pro	synonymous	Exon 18 of 58	NP_001035957.1	P21359-1
	NF1	NM_000267.4		c.2034G>A	p.Pro678Pro	synonymous	Exon 18 of 57	NP_000258.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.2034G>A	p.Pro678Pro	synonymous	Exon 18 of 58	ENSP00000351015.4	P21359-1
	NF1	ENST00000356175.7	TSL:1	c.2034G>A	p.Pro678Pro	synonymous	Exon 18 of 57	ENSP00000348498.3	P21359-2
	NF1	ENST00000579081.6	TSL:1	n.2034G>A		non_coding_transcript_exon	Exon 18 of 58	ENSP00000462408.2	J3KSB5

Frequencies

GnomAD3 genomes AF: 0.425 AC: 64514 AN: 151726 Hom.: 15853 Cov.: 31

Gnomad AFR AF: 0.674

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.433

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.524

Gnomad SAS AF: 0.382

Gnomad FIN AF: 0.343

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.363

GnomAD2 exomes AF: 0.378 AC: 94603 AN: 250420 AF XY: 0.362

Gnomad AFR exome AF: 0.683

Gnomad AMR exome AF: 0.494

Gnomad ASJ exome AF: 0.226

Gnomad EAS exome AF: 0.519

Gnomad FIN exome AF: 0.338

Gnomad NFE exome AF: 0.301

Gnomad OTH exome AF: 0.330

GnomAD4 exome AF: 0.327 AC: 477803 AN: 1461402 Hom.: 83400 Cov.: 52 AF XY: 0.326 AC XY: 236867 AN XY: 726990

African (AFR) AF: 0.686 AC: 22964 AN: 33456

American (AMR) AF: 0.485 AC: 21651 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 5962 AN: 26126

East Asian (EAS) AF: 0.540 AC: 21416 AN: 39688

South Asian (SAS) AF: 0.368 AC: 31705 AN: 86246

European-Finnish (FIN) AF: 0.343 AC: 18306 AN: 53396

Middle Eastern (MID) AF: 0.226 AC: 1302 AN: 5762

European-Non Finnish (NFE) AF: 0.301 AC: 334344 AN: 1111702

Other (OTH) AF: 0.334 AC: 20153 AN: 60356

GnomAD4 genome AF: 0.425 AC: 64585 AN: 151844 Hom.: 15875 Cov.: 31 AF XY: 0.430 AC XY: 31920 AN XY: 74218

African (AFR) AF: 0.673 AC: 27870 AN: 41382

American (AMR) AF: 0.433 AC: 6601 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 812 AN: 3466

East Asian (EAS) AF: 0.524 AC: 2708 AN: 5164

South Asian (SAS) AF: 0.383 AC: 1847 AN: 4818

European-Finnish (FIN) AF: 0.343 AC: 3603 AN: 10516

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.295 AC: 20067 AN: 67954

Other (OTH) AF: 0.363 AC: 762 AN: 2102

Alfa AF: 0.318 Hom.: 5705

Bravo AF: 0.442

Asia WGS AF: 0.462 AC: 1605 AN: 3478

EpiCase AF: 0.279

EpiControl AF: 0.278

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	-	4	Neurofibromatosis, type 1 (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Neurofibromatosis, familial spinal (2)
-	-	1	Café-au-lait macules with pulmonary stenosis (1)
-	-	1	Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype (1)
-	-	1	Neurofibromatosis-Noonan syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	3.6
DANN	Benign	0.56
PhyloP100		-1.3
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2285892; hg19: chr17-29553485; COSMIC: COSV62191601; COSMIC: COSV62191601;