rs17883704

Variant names:

• chr17-31229159-G-A
• rs17883704
• NM_001042492.3:c.2544G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-31229159-G-A
• chr17-31229159-G-C
• chr17-31229159-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.2544G>A​(p.Gly848Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00451 in 1,611,892 control chromosomes in the GnomAD database, including 310 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. G848G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.024 (164 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (146 hom.)
• Consequence: NF1 NM_001042492.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: -0.616
• Publications: 8 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=-0.55).
• BP6: Variant 17-31229159-G-A is Benign according to our data. Variant chr17-31229159-G-A is described in ClinVar as Benign. ClinVar VariationId is 183949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.616 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0796 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.2544G>A	p.Gly848Gly	synonymous	Exon 21 of 58	NP_001035957.1	P21359-1
	NF1	NM_000267.4		c.2544G>A	p.Gly848Gly	synonymous	Exon 21 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.2544G>A	p.Gly848Gly	synonymous	Exon 21 of 58	ENSP00000351015.4	P21359-1
	NF1	ENST00000356175.7	TSL:1	c.2544G>A	p.Gly848Gly	synonymous	Exon 21 of 57	ENSP00000348498.3	P21359-2
	NF1	ENST00000579081.6	TSL:1	n.2544G>A		non_coding_transcript_exon	Exon 21 of 58	ENSP00000462408.2	J3KSB5

Frequencies

GnomAD3 genomes AF: 0.0233 AC: 3552 AN: 152194 Hom.: 152 Cov.: 32

Gnomad AFR AF: 0.0809

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00910

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.00579 AC: 1451 AN: 250520 AF XY: 0.00411

Gnomad AFR exome AF: 0.0779

Gnomad AMR exome AF: 0.00394

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00251 AC: 3668 AN: 1459580 Hom.: 146 Cov.: 32 AF XY: 0.00214 AC XY: 1555 AN XY: 726096

African (AFR) AF: 0.0844 AC: 2820 AN: 33396

American (AMR) AF: 0.00479 AC: 214 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000348 AC: 30 AN: 86162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00701 AC: 29 AN: 4136

European-Non Finnish (NFE) AF: 0.000169 AC: 188 AN: 1111780

Other (OTH) AF: 0.00643 AC: 387 AN: 60196

GnomAD4 genome AF: 0.0237 AC: 3605 AN: 152312 Hom.: 164 Cov.: 32 AF XY: 0.0234 AC XY: 1739 AN XY: 74470

African (AFR) AF: 0.0819 AC: 3405 AN: 41558

American (AMR) AF: 0.00909 AC: 139 AN: 15298

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

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

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

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

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

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68028

Other (OTH) AF: 0.0175 AC: 37 AN: 2116

Alfa AF: 0.0122 Hom.: 35

Bravo AF: 0.0256

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Neurofibromatosis, type 1 (5)
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	2	Neurofibromatosis, familial spinal (2)
-	-	1	Café-au-lait macules with pulmonary stenosis (1)
-	-	1	Hereditary cancer-predisposing syndrome (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	-0.55
CADD	Benign	7.6
DANN	Benign	0.69
PhyloP100		-0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs17883704; hg19: chr17-29556177; COSMIC: COSV62196919;