rs1801052

Variant names:

• chr17-31181757-G-A
• rs1801052
• NM_001042492.3:c.702G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-31181757-G-A
• chr17-31181757-G-T

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.702G>A​(p.Leu234Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.665 in 1,604,776 control chromosomes in the GnomAD database, including 363,710 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. L234L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.57 (26997 hom., cov: 29)
  • Exomes 𝑓: 0.68 (336713 hom.)
• Consequence: NF1 NM_001042492.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: -1.86
• Publications: 74 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=-0.83).
• BP6: Variant 17-31181757-G-A is Benign according to our data. Variant chr17-31181757-G-A is described in ClinVar as Benign. ClinVar VariationId is 183825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.86 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.699 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.702G>A	p.Leu234Leu	synonymous	Exon 7 of 58	NP_001035957.1	P21359-1
	NF1	NM_000267.4		c.702G>A	p.Leu234Leu	synonymous	Exon 7 of 57	NP_000258.1
	NF1	NM_001128147.3		c.702G>A	p.Leu234Leu	synonymous	Exon 7 of 15	NP_001121619.1	P21359-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.702G>A	p.Leu234Leu	synonymous	Exon 7 of 58	ENSP00000351015.4	P21359-1
	NF1	ENST00000356175.7	TSL:1	c.702G>A	p.Leu234Leu	synonymous	Exon 7 of 57	ENSP00000348498.3	P21359-2
	NF1	ENST00000431387.8	TSL:1	c.702G>A	p.Leu234Leu	synonymous	Exon 7 of 15	ENSP00000412921.4	P21359-5

Frequencies

GnomAD3 genomes AF: 0.572 AC: 86258 AN: 150814 Hom.: 26990 Cov.: 29

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.720

Gnomad AMR AF: 0.565

Gnomad ASJ AF: 0.768

Gnomad EAS AF: 0.562

Gnomad SAS AF: 0.627

Gnomad FIN AF: 0.660

Gnomad MID AF: 0.779

Gnomad NFE AF: 0.704

Gnomad OTH AF: 0.631

GnomAD2 exomes AF: 0.627 AC: 157498 AN: 251116 AF XY: 0.643

Gnomad AFR exome AF: 0.290

Gnomad AMR exome AF: 0.507

Gnomad ASJ exome AF: 0.776

Gnomad EAS exome AF: 0.561

Gnomad FIN exome AF: 0.662

Gnomad NFE exome AF: 0.698

Gnomad OTH exome AF: 0.671

GnomAD4 exome AF: 0.675 AC: 981504 AN: 1453854 Hom.: 336713 Cov.: 37 AF XY: 0.676 AC XY: 489500 AN XY: 723658

African (AFR) AF: 0.286 AC: 9522 AN: 33334

American (AMR) AF: 0.516 AC: 23060 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.775 AC: 20198 AN: 26060

East Asian (EAS) AF: 0.555 AC: 21964 AN: 39556

South Asian (SAS) AF: 0.637 AC: 54841 AN: 86034

European-Finnish (FIN) AF: 0.657 AC: 35068 AN: 53406

Middle Eastern (MID) AF: 0.768 AC: 4374 AN: 5698

European-Non Finnish (NFE) AF: 0.699 AC: 772272 AN: 1104988

Other (OTH) AF: 0.669 AC: 40205 AN: 60096

GnomAD4 genome AF: 0.572 AC: 86299 AN: 150922 Hom.: 26997 Cov.: 29 AF XY: 0.568 AC XY: 41858 AN XY: 73630

African (AFR) AF: 0.304 AC: 12476 AN: 41056

American (AMR) AF: 0.565 AC: 8575 AN: 15174

Ashkenazi Jewish (ASJ) AF: 0.768 AC: 2664 AN: 3468

East Asian (EAS) AF: 0.562 AC: 2872 AN: 5114

South Asian (SAS) AF: 0.626 AC: 3003 AN: 4796

European-Finnish (FIN) AF: 0.660 AC: 6731 AN: 10194

Middle Eastern (MID) AF: 0.777 AC: 227 AN: 292

European-Non Finnish (NFE) AF: 0.704 AC: 47768 AN: 67816

Other (OTH) AF: 0.632 AC: 1328 AN: 2102

Alfa AF: 0.647 Hom.: 82021

Bravo AF: 0.554

Asia WGS AF: 0.578 AC: 2007 AN: 3472

EpiCase AF: 0.720

EpiControl AF: 0.721

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	Neurofibromatosis, type 1 (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	not provided (3)
-	-	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	-0.83
CADD	Benign	0.042
DANN	Benign	0.65
PhyloP100		-1.9
PromoterAI		-0.0086	Neutral
Mutation Taster		=80/20	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: rs1801052; hg19: chr17-29508775; COSMIC: COSV62193259;