rs12603885

Variant names:

• chr17-31139704-G-A
• rs12603885
• NM_001042492.3:c.61-16279G>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.61-16279G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.561 in 151,974 control chromosomes in the GnomAD database, including 26,703 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 0.56 (26703 hom., cov: 31)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.619
• Publications: 9 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=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.61-16279G>A		intron_variant	Intron 1 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.61-16279G>A		intron_variant	Intron 1 of 56		NP_000258.1
NF1	NM_001128147.3	c.61-16279G>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.61-16279G>A		intron_variant	Intron 1 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.562 AC: 85305 AN: 151856 Hom.: 26710 Cov.: 31

Gnomad AFR AF: 0.269

Gnomad AMI AF: 0.720

Gnomad AMR AF: 0.562

Gnomad ASJ AF: 0.768

Gnomad EAS AF: 0.563

Gnomad SAS AF: 0.622

Gnomad FIN AF: 0.657

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.705

Gnomad OTH AF: 0.623

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

GnomAD4 genome AF: 0.561 AC: 85305 AN: 151974 Hom.: 26703 Cov.: 31 AF XY: 0.558 AC XY: 41436 AN XY: 74278

African (AFR) AF: 0.269 AC: 11149 AN: 41438

American (AMR) AF: 0.562 AC: 8574 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.768 AC: 2667 AN: 3472

East Asian (EAS) AF: 0.562 AC: 2898 AN: 5160

South Asian (SAS) AF: 0.620 AC: 2990 AN: 4820

European-Finnish (FIN) AF: 0.657 AC: 6928 AN: 10542

Middle Eastern (MID) AF: 0.786 AC: 231 AN: 294

European-Non Finnish (NFE) AF: 0.705 AC: 47897 AN: 67974

Other (OTH) AF: 0.623 AC: 1314 AN: 2108

Alfa AF: 0.568 Hom.: 5011

Bravo AF: 0.544

Asia WGS AF: 0.574 AC: 1998 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.39
DANN	Benign	0.57
PhyloP100		-0.62
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: rs12603885; hg19: chr17-29466722;