rs17880521

Variant names:

• chr17-31325913-G-A
• rs17880521
• NM_001042492.3:c.4929G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-31325913-G-A
• chr17-31325913-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001042492.3(NF1):​c.4929G>A​(p.Val1643Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00457 in 1,614,072 control chromosomes in the GnomAD database, including 86 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. V1643V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.014 (43 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (43 hom.)
• Consequence: NF1 NM_001042492.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 2.17
• Publications: 12 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 17-31325913-G-A is Benign according to our data. Variant chr17-31325913-G-A is described in ClinVar as Benign. ClinVar VariationId is 184149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.17 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0144 (2188/152250) while in subpopulation AFR AF = 0.0427 (1772/41526). AF 95% confidence interval is 0.041. There are 43 homozygotes in GnomAd4. There are 1048 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2188 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.4929G>A	p.Val1643Val	synonymous	Exon 37 of 58	NP_001035957.1
	NF1	NM_000267.4		c.4866G>A	p.Val1622Val	synonymous	Exon 36 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.4929G>A	p.Val1643Val	synonymous	Exon 37 of 58	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.4866G>A	p.Val1622Val	synonymous	Exon 36 of 57	ENSP00000348498.3
	NF1	ENST00000579081.6	TSL:1	n.*94G>A		non_coding_transcript_exon	Exon 37 of 58	ENSP00000462408.2

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2185 AN: 152132 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.0427

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0133

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00209

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.00525 AC: 1319 AN: 251306 AF XY: 0.00439

Gnomad AFR exome AF: 0.0443

Gnomad AMR exome AF: 0.00503

Gnomad ASJ exome AF: 0.00685

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00254

Gnomad OTH exome AF: 0.00783

GnomAD4 exome AF: 0.00355 AC: 5194 AN: 1461822 Hom.: 43 Cov.: 32 AF XY: 0.00340 AC XY: 2470 AN XY: 727204

African (AFR) AF: 0.0481 AC: 1610 AN: 33476

American (AMR) AF: 0.00581 AC: 260 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00727 AC: 190 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000742 AC: 64 AN: 86256

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53420

Middle Eastern (MID) AF: 0.0139 AC: 80 AN: 5768

European-Non Finnish (NFE) AF: 0.00234 AC: 2602 AN: 1111948

Other (OTH) AF: 0.00633 AC: 382 AN: 60394

GnomAD4 genome AF: 0.0144 AC: 2188 AN: 152250 Hom.: 43 Cov.: 32 AF XY: 0.0141 AC XY: 1048 AN XY: 74440

African (AFR) AF: 0.0427 AC: 1772 AN: 41526

American (AMR) AF: 0.0133 AC: 203 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 24 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00209 AC: 142 AN: 68024

Other (OTH) AF: 0.0156 AC: 33 AN: 2116

Alfa AF: 0.00967 Hom.: 18

Bravo AF: 0.0172

Asia WGS AF: 0.00318 AC: 12 AN: 3478

EpiCase AF: 0.00371

EpiControl AF: 0.00296

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Neurofibromatosis, type 1 (5)
-	-	5	not provided (5)
-	-	4	not specified (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)
-	-	1	Neurofibromatosis, type 1;C0349639:Juvenile myelomonocytic leukemia;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	6.8
DANN	Benign	0.76
PhyloP100		2.2
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: rs17880521; hg19: chr17-29652931; COSMIC: COSV55986970;