rs2285894

Variant names:

• chr17-31327858-T-A
• rs2285894
• NM_001042492.3:c.5609+19T>A

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.5609+19T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 1,605,644 control chromosomes in the GnomAD database, including 278,086 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (20825 hom., cov: 31)
  • Exomes 𝑓: 0.59 (257261 hom.)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.06

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 (BayesDel_noAF=-0.89).
• BP6: Variant 17-31327858-T-A is Benign according to our data. Variant chr17-31327858-T-A is described in ClinVar as [Benign]. Clinvar id is 257294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31327858-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.5609+19T>A		intron_variant	Intron 38 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.5546+19T>A		intron_variant	Intron 37 of 56		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.5609+19T>A		intron_variant	Intron 38 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.502 AC: 76225 AN: 151886 Hom.: 20816 Cov.: 31

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.678

Gnomad AMR AF: 0.446

Gnomad ASJ AF: 0.684

Gnomad EAS AF: 0.358

Gnomad SAS AF: 0.563

Gnomad FIN AF: 0.601

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.619

Gnomad OTH AF: 0.531

GnomAD3 exomes AF: 0.535 AC: 133633 AN: 249712 Hom.: 37686 AF XY: 0.551 AC XY: 74557 AN XY: 135196

Gnomad AFR exome AF: 0.285

Gnomad AMR exome AF: 0.377

Gnomad ASJ exome AF: 0.686

Gnomad EAS exome AF: 0.356

Gnomad SAS exome AF: 0.572

Gnomad FIN exome AF: 0.600

Gnomad NFE exome AF: 0.611

Gnomad OTH exome AF: 0.567

GnomAD4 exome AF: 0.589 AC: 856724 AN: 1453640 Hom.: 257261 Cov.: 30 AF XY: 0.591 AC XY: 427869 AN XY: 723682

Gnomad4 AFR exome AF: 0.280

Gnomad4 AMR exome AF: 0.388

Gnomad4 ASJ exome AF: 0.687

Gnomad4 EAS exome AF: 0.375

Gnomad4 SAS exome AF: 0.576

Gnomad4 FIN exome AF: 0.596

Gnomad4 NFE exome AF: 0.614

Gnomad4 OTH exome AF: 0.573

GnomAD4 genome AF: 0.502 AC: 76260 AN: 152004 Hom.: 20825 Cov.: 31 AF XY: 0.499 AC XY: 37069 AN XY: 74296

Gnomad4 AFR AF: 0.294

Gnomad4 AMR AF: 0.446

Gnomad4 ASJ AF: 0.684

Gnomad4 EAS AF: 0.358

Gnomad4 SAS AF: 0.561

Gnomad4 FIN AF: 0.601

Gnomad4 NFE AF: 0.619

Gnomad4 OTH AF: 0.528

Alfa AF: 0.569 Hom.: 4707

Bravo AF: 0.480

Asia WGS AF: 0.438 AC: 1523 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 25, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 18, 2015

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. -

Neurofibromatosis, type 1 Benign:3

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 12, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The NF1 c.5546+19T>A variant involves the alteration of a non-conserved intronic nucleotide with 5/5 splice prediction tools calculating no significant effect on splicing, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 64462/120180 (18196 homozygotes, frequency: 0.5363788), which suggests that the variant of interest is the major allele (most common allele observed in the general population. Therefore, the variant of interest is classified as Benign. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Neurofibromatosis, familial spinal Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.21
DANN	Benign	0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2285894; hg19: chr17-29654876; COSMIC: COSV62205010; COSMIC: COSV62205010;