17-31182783-G-T

Variant names:

• chr17-31182783-G-T
• rs2952999
• NM_001042492.3:c.888+118G>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001042492.3(NF1):​c.888+118G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.65 in 984,026 control chromosomes in the GnomAD database, including 215,062 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (26643 hom., cov: 33)
  • Exomes 𝑓: 0.67 (188419 hom.)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.755

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046660304).
• BP6: Variant 17-31182783-G-T is Benign according to our data. Variant chr17-31182783-G-T is described in ClinVar as [Benign]. Clinvar id is 561466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.888+118G>T		intron_variant	Intron 8 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.888+118G>T		intron_variant	Intron 8 of 56		NP_000258.1
NF1	NM_001128147.3	c.888+118G>T		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.888+118G>T		intron_variant	Intron 8 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.566 AC: 85784 AN: 151538 Hom.: 26633 Cov.: 33

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.719

Gnomad AMR AF: 0.563

Gnomad ASJ AF: 0.766

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.617

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.703

Gnomad OTH AF: 0.627

GnomAD4 exome AF: 0.665 AC: 553546 AN: 832366 Hom.: 188419 Cov.: 11 AF XY: 0.666 AC XY: 286535 AN XY: 430210

Gnomad4 AFR exome AF: 0.294

Gnomad4 AMR exome AF: 0.521

Gnomad4 ASJ exome AF: 0.772

Gnomad4 EAS exome AF: 0.456

Gnomad4 SAS exome AF: 0.633

Gnomad4 FIN exome AF: 0.653

Gnomad4 NFE exome AF: 0.699

Gnomad4 OTH exome AF: 0.661

GnomAD4 genome AF: 0.566 AC: 85831 AN: 151660 Hom.: 26643 Cov.: 33 AF XY: 0.562 AC XY: 41620 AN XY: 74098

Gnomad4 AFR AF: 0.302

Gnomad4 AMR AF: 0.563

Gnomad4 ASJ AF: 0.766

Gnomad4 EAS AF: 0.471

Gnomad4 SAS AF: 0.615

Gnomad4 FIN AF: 0.653

Gnomad4 NFE AF: 0.703

Gnomad4 OTH AF: 0.627

Alfa AF: 0.606 Hom.: 4363

Bravo AF: 0.549

TwinsUK AF: 0.694 AC: 2573

ALSPAC AF: 0.696 AC: 2684

Asia WGS AF: 0.533 AC: 1856 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 20, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	14
DANN	Benign	0.69
FATHMM_MKL	Benign	0.0048	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.0047	T
GERP RS		-0.90

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

Publications

LitVar

Other links and lift over

dbSNP: rs2952999; hg19: chr17-29509801; COSMIC: COSV62206121;