rs4795587

Variant names:

• chr17-31260899-A-C
• rs4795587
• NM_001042492.3:c.4577+384A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001042492.3(NF1):​c.4577+384A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.369 in 151,972 control chromosomes in the GnomAD database, including 10,905 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.37 (10905 hom., cov: 31)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.20
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.526 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.4577+384A>C		intron_variant	Intron 34 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.4514+384A>C		intron_variant	Intron 33 of 56		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.4577+384A>C		intron_variant	Intron 34 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.369 AC: 56074 AN: 151854 Hom.: 10886 Cov.: 31

Gnomad AFR AF: 0.463

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.425

Gnomad ASJ AF: 0.235

Gnomad EAS AF: 0.542

Gnomad SAS AF: 0.382

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.191

Gnomad NFE AF: 0.299

Gnomad OTH AF: 0.328

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.369 AC: 56125 AN: 151972 Hom.: 10905 Cov.: 31 AF XY: 0.376 AC XY: 27934 AN XY: 74268

African (AFR) AF: 0.463 AC: 19174 AN: 41438

American (AMR) AF: 0.426 AC: 6488 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.235 AC: 815 AN: 3462

East Asian (EAS) AF: 0.543 AC: 2798 AN: 5156

South Asian (SAS) AF: 0.384 AC: 1852 AN: 4824

European-Finnish (FIN) AF: 0.351 AC: 3700 AN: 10554

Middle Eastern (MID) AF: 0.192 AC: 56 AN: 292

European-Non Finnish (NFE) AF: 0.299 AC: 20300 AN: 67984

Other (OTH) AF: 0.328 AC: 690 AN: 2106

Alfa AF: 0.351 Hom.: 1197

Bravo AF: 0.377

Asia WGS AF: 0.457 AC: 1587 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.3
DANN	Benign	0.45
PhyloP100		-1.2
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: rs4795587; hg19: chr17-29587917;