rs2905787

Variant names:

• chr17-31155363-G-A
• rs2905787
• NM_001042492.3:c.61-620G>A

Variant summary

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

The NM_001042492.3(NF1):​c.61-620G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.712 in 151,994 control chromosomes in the GnomAD database, including 38,877 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 0.71 (38877 hom., cov: 31)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.956
• Publications: 4 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=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.756 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.61-620G>A		intron_variant	Intron 1 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.61-620G>A		intron_variant	Intron 1 of 56		NP_000258.1
NF1	NM_001128147.3	c.61-620G>A		intron_variant	Intron 1 of 14		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.61-620G>A		intron_variant	Intron 1 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.712 AC: 108171 AN: 151876 Hom.: 38849 Cov.: 31

Gnomad AFR AF: 0.763

Gnomad AMI AF: 0.741

Gnomad AMR AF: 0.627

Gnomad ASJ AF: 0.785

Gnomad EAS AF: 0.562

Gnomad SAS AF: 0.663

Gnomad FIN AF: 0.672

Gnomad MID AF: 0.835

Gnomad NFE AF: 0.716

Gnomad OTH AF: 0.745

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

GnomAD4 genome AF: 0.712 AC: 108245 AN: 151994 Hom.: 38877 Cov.: 31 AF XY: 0.705 AC XY: 52410 AN XY: 74292

African (AFR) AF: 0.763 AC: 31644 AN: 41456

American (AMR) AF: 0.627 AC: 9572 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.785 AC: 2724 AN: 3468

East Asian (EAS) AF: 0.561 AC: 2890 AN: 5154

South Asian (SAS) AF: 0.661 AC: 3184 AN: 4816

European-Finnish (FIN) AF: 0.672 AC: 7087 AN: 10546

Middle Eastern (MID) AF: 0.837 AC: 246 AN: 294

European-Non Finnish (NFE) AF: 0.716 AC: 48650 AN: 67962

Other (OTH) AF: 0.744 AC: 1574 AN: 2116

Alfa AF: 0.703 Hom.: 4681

Bravo AF: 0.713

Asia WGS AF: 0.620 AC: 2154 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.5
DANN	Benign	0.19
PhyloP100		0.96
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: rs2905787; hg19: chr17-29482381;