rs17886566

Variant names:

• chr17-31258439-A-G
• rs17886566
• NM_001042492.3:c.4269A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-31258439-A-G
• chr17-31258439-A-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001042492.3(NF1):​c.4269A>G​(p.Glu1423Glu) variant causes a synonymous change. The variant allele was found at a frequency of 0.000401 in 1,613,968 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (2 hom.)
• Consequence: NF1 NM_001042492.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 5.29
• Publications: 3 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 17-31258439-A-G is Benign according to our data. Variant chr17-31258439-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 184231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00219 (333/152276) while in subpopulation AFR AF = 0.00763 (317/41570). AF 95% confidence interval is 0.00693. There are 0 homozygotes in GnomAd4. There are 161 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 333 AD gene.

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.4269A>G	p.Glu1423Glu	synonymous	Exon 32 of 58	NP_001035957.1	P21359-1
	NF1	NM_000267.4		c.4206A>G	p.Glu1402Glu	synonymous	Exon 31 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.4269A>G	p.Glu1423Glu	synonymous	Exon 32 of 58	ENSP00000351015.4	P21359-1
	NF1	ENST00000356175.7	TSL:1	c.4206A>G	p.Glu1402Glu	synonymous	Exon 31 of 57	ENSP00000348498.3	P21359-2
	NF1	ENST00000579081.6	TSL:1	n.4206A>G		non_coding_transcript_exon	Exon 31 of 58	ENSP00000462408.2	J3KSB5

Frequencies

GnomAD3 genomes AF: 0.00217 AC: 330 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00758

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000597 AC: 150 AN: 251288 AF XY: 0.000479

Gnomad AFR exome AF: 0.00824

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000216 AC: 315 AN: 1461692 Hom.: 2 Cov.: 31 AF XY: 0.000193 AC XY: 140 AN XY: 727140

African (AFR) AF: 0.00786 AC: 263 AN: 33476

American (AMR) AF: 0.000447 AC: 20 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111894

Other (OTH) AF: 0.000431 AC: 26 AN: 60388

GnomAD4 genome AF: 0.00219 AC: 333 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.00216 AC XY: 161 AN XY: 74470

African (AFR) AF: 0.00763 AC: 317 AN: 41570

American (AMR) AF: 0.000785 AC: 12 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000760 Hom.: 0

Bravo AF: 0.00271

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	3	Neurofibromatosis, type 1 (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Neurofibromatosis, familial spinal (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	12
DANN	Benign	0.64
PhyloP100		5.3
Mutation Taster		=100/0	polymorphism

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: rs17886566; hg19: chr17-29585457; COSMIC: COSV104662405;