NM_001042492.3:c.*2265C>G

Variant names:

• chr17-31376420-C-G
• rs1800845
• NM_001042492.3:c.*2265C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001042492.3(NF1):​c.*2265C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.442 in 232,422 control chromosomes in the GnomAD database, including 28,525 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (22203 hom., cov: 32)
  • Exomes 𝑓: 0.36 (6322 hom.)
• Consequence: NF1 NM_001042492.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.897
• Publications: 17 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 17-31376420-C-G is Benign according to our data. Variant chr17-31376420-C-G is described in ClinVar as Benign. ClinVar VariationId is 322599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.85 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.*2265C>G		3_prime_UTR	Exon 58 of 58	NP_001035957.1	P21359-1
	NF1	NM_000267.4		c.*2265C>G		3_prime_UTR	Exon 57 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.*2265C>G		3_prime_UTR	Exon 58 of 58	ENSP00000351015.4	P21359-1
	NF1	ENST00000356175.7	TSL:1	c.*2265C>G		3_prime_UTR	Exon 57 of 57	ENSP00000348498.3	P21359-2
	NF1	ENST00000691014.1		c.*2265C>G		3_prime_UTR	Exon 59 of 59	ENSP00000510595.1	A0A8I5KWR6

Frequencies

GnomAD3 genomes AF: 0.482 AC: 73298 AN: 151956 Hom.: 22137 Cov.: 32

Gnomad AFR AF: 0.857

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.537

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.345

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.299

Gnomad OTH AF: 0.410

GnomAD4 exome AF: 0.364 AC: 29243 AN: 80348 Hom.: 6322 Cov.: 0 AF XY: 0.358 AC XY: 13214 AN XY: 36936

African (AFR) AF: 0.856 AC: 3311 AN: 3866

American (AMR) AF: 0.481 AC: 1196 AN: 2484

Ashkenazi Jewish (ASJ) AF: 0.235 AC: 1193 AN: 5082

East Asian (EAS) AF: 0.559 AC: 6322 AN: 11306

South Asian (SAS) AF: 0.384 AC: 267 AN: 696

European-Finnish (FIN) AF: 0.276 AC: 16 AN: 58

Middle Eastern (MID) AF: 0.244 AC: 120 AN: 492

European-Non Finnish (NFE) AF: 0.289 AC: 14323 AN: 49644

Other (OTH) AF: 0.371 AC: 2495 AN: 6720

GnomAD4 genome AF: 0.483 AC: 73430 AN: 152074 Hom.: 22203 Cov.: 32 AF XY: 0.486 AC XY: 36112 AN XY: 74328

African (AFR) AF: 0.858 AC: 35605 AN: 41504

American (AMR) AF: 0.470 AC: 7189 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 823 AN: 3472

East Asian (EAS) AF: 0.537 AC: 2776 AN: 5166

South Asian (SAS) AF: 0.387 AC: 1865 AN: 4822

European-Finnish (FIN) AF: 0.345 AC: 3642 AN: 10550

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.299 AC: 20336 AN: 67958

Other (OTH) AF: 0.409 AC: 864 AN: 2112

Alfa AF: 0.410 Hom.: 2054

Bravo AF: 0.506

Asia WGS AF: 0.486 AC: 1691 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Café-au-lait macules with pulmonary stenosis (1)
-	-	1	Neurofibromatosis-Noonan syndrome (1)
-	-	1	Neurofibromatosis, familial spinal (1)
-	-	1	Neurofibromatosis, type 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.7
DANN	Benign	0.63
PhyloP100		0.90
Mutation Taster		=100/0	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: rs1800845; hg19: chr17-29703438;