17-31199724-T-C

Variant names:

• chr17-31199724-T-C
• rs2952991
• NM_001042492.3:c.889-698T>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.889-698T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.552 in 152,042 control chromosomes in the GnomAD database, including 26,329 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 0.55 (26329 hom., cov: 32)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0450
• Publications: 11 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=-0.87).
• 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.889-698T>C		intron_variant	Intron 8 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.889-698T>C		intron_variant	Intron 8 of 56		NP_000258.1
NF1	NM_001128147.3	c.889-698T>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.889-698T>C		intron_variant	Intron 8 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.552 AC: 83901 AN: 151924 Hom.: 26330 Cov.: 32

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.720

Gnomad AMR AF: 0.558

Gnomad ASJ AF: 0.768

Gnomad EAS AF: 0.562

Gnomad SAS AF: 0.628

Gnomad FIN AF: 0.658

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.704

Gnomad OTH AF: 0.617

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

GnomAD4 genome AF: 0.552 AC: 83926 AN: 152042 Hom.: 26329 Cov.: 32 AF XY: 0.549 AC XY: 40825 AN XY: 74324

African (AFR) AF: 0.237 AC: 9842 AN: 41474

American (AMR) AF: 0.558 AC: 8524 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.768 AC: 2666 AN: 3470

East Asian (EAS) AF: 0.561 AC: 2906 AN: 5178

South Asian (SAS) AF: 0.626 AC: 3016 AN: 4818

European-Finnish (FIN) AF: 0.658 AC: 6932 AN: 10536

Middle Eastern (MID) AF: 0.755 AC: 222 AN: 294

European-Non Finnish (NFE) AF: 0.704 AC: 47857 AN: 67968

Other (OTH) AF: 0.617 AC: 1304 AN: 2112

Alfa AF: 0.597 Hom.: 4147

Bravo AF: 0.533

Asia WGS AF: 0.574 AC: 1997 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	8.9
DANN	Benign	0.74
PhyloP100		-0.045
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: rs2952991; hg19: chr17-29526742;