rs2269855

chr17-31155860-G-Achr17-31155860-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001042492.3(NF1):c.61-123G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.661 in 1,102,578 control chromosomes in the GnomAD database, including 247,481 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.57 (27088 hom., cov: 32)
  • Exomes 𝑓: 0.68 (220393 hom.)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.854

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 17-31155860-G-A is Benign according to our data. Variant chr17-31155860-G-A is described in ClinVar as [Benign]. Clinvar id is 561463.Status of the report is criteria_provided_single_submitter, 1 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/exons	MANE	UniProt
NF1	NM_001042492.3	c.61-123G>A		intron_variant		ENST00000358273.9
NF1	NM_000267.3	c.61-123G>A		intron_variant
NF1	NM_001128147.3	c.61-123G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.61-123G>A		intron_variant		1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes AF: 0.570 AC: 86627 AN: 151860 Hom.: 27081 Cov.: 32

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.722

Gnomad AMR AF: 0.565

Gnomad ASJ AF: 0.768

Gnomad EAS AF: 0.562

Gnomad SAS AF: 0.621

Gnomad FIN AF: 0.656

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.704

Gnomad OTH AF: 0.628

GnomAD4 exome AF: 0.676 AC: 642426 AN: 950600 Hom.: 220393 AF XY: 0.676 AC XY: 327996 AN XY: 485216

Gnomad4 AFR exome AF: 0.294

Gnomad4 AMR exome AF: 0.523

Gnomad4 ASJ exome AF: 0.775

Gnomad4 EAS exome AF: 0.557

Gnomad4 SAS exome AF: 0.633

Gnomad4 FIN exome AF: 0.653

Gnomad4 NFE exome AF: 0.702

Gnomad4 OTH exome AF: 0.669

GnomAD4 genome AF: 0.570 AC: 86667 AN: 151978 Hom.: 27088 Cov.: 32 AF XY: 0.567 AC XY: 42123 AN XY: 74298

Gnomad4 AFR AF: 0.303

Gnomad4 AMR AF: 0.564

Gnomad4 ASJ AF: 0.768

Gnomad4 EAS AF: 0.561

Gnomad4 SAS AF: 0.620

Gnomad4 FIN AF: 0.656

Gnomad4 NFE AF: 0.704

Gnomad4 OTH AF: 0.629

Alfa AF: 0.607 Hom.: 4377

Bravo AF: 0.553

Asia WGS AF: 0.577 AC: 2006 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 20, 2018

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	-0.88
Cadd	Benign	4.0
Dann	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2269855; hg19: chr17-29482878; COSMIC: COSV62206109; COSMIC: COSV62206109;