17-31192977-T-C

Variant names:

• chr17-31192977-T-C
• rs2905804
• NM_001042492.3:c.889-7445T>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.889-7445T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.702 in 152,024 control chromosomes in the GnomAD database, including 37,714 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 0.70 (37714 hom., cov: 31)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.93
• Publications: 6 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=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.719 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.889-7445T>C		intron_variant	Intron 8 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.889-7445T>C		intron_variant	Intron 8 of 56		NP_000258.1
NF1	NM_001128147.3	c.889-7445T>C		intron_variant	Intron 8 of 14		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.889-7445T>C		intron_variant	Intron 8 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.702 AC: 106631 AN: 151906 Hom.: 37686 Cov.: 31

Gnomad AFR AF: 0.726

Gnomad AMI AF: 0.741

Gnomad AMR AF: 0.623

Gnomad ASJ AF: 0.786

Gnomad EAS AF: 0.563

Gnomad SAS AF: 0.669

Gnomad FIN AF: 0.672

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.716

Gnomad OTH AF: 0.739

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

GnomAD4 genome AF: 0.702 AC: 106704 AN: 152024 Hom.: 37714 Cov.: 31 AF XY: 0.695 AC XY: 51658 AN XY: 74282

African (AFR) AF: 0.726 AC: 30105 AN: 41466

American (AMR) AF: 0.623 AC: 9510 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.786 AC: 2728 AN: 3472

East Asian (EAS) AF: 0.562 AC: 2905 AN: 5172

South Asian (SAS) AF: 0.667 AC: 3218 AN: 4826

European-Finnish (FIN) AF: 0.672 AC: 7076 AN: 10532

Middle Eastern (MID) AF: 0.840 AC: 247 AN: 294

European-Non Finnish (NFE) AF: 0.716 AC: 48685 AN: 67976

Other (OTH) AF: 0.738 AC: 1557 AN: 2110

Alfa AF: 0.697 Hom.: 4575

Bravo AF: 0.701

Asia WGS AF: 0.620 AC: 2155 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	0.54
DANN	Benign	0.54
PhyloP100		-1.9
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: rs2905804; hg19: chr17-29519995;