rs17887014

Positions:

• chr17-31326219-G-A
• chr17-31326219-G-C
• chr17-31326219-G-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001042492.3(NF1):​c.5235G>A​(p.Lys1745Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00384 in 1,611,832 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (25 hom.)
• Consequence: NF1 NM_001042492.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26
• Conservation: PhyloP100: 1.25

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 17-31326219-G-A is Benign according to our data. Variant chr17-31326219-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 184131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31326219-G-A is described in Lovd as [Benign]. Variant chr17-31326219-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.25 with no splicing effect.
• BS2: High AC in GnomAd4 at 461 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.5235G>A	p.Lys1745Lys	synonymous_variant	37/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.5172G>A	p.Lys1724Lys	synonymous_variant	36/57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.5235G>A	p.Lys1745Lys	synonymous_variant	37/58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.00303 AC: 461 AN: 152202 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.00349

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00528

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00307 AC: 762 AN: 247988 Hom.: 3 AF XY: 0.00319 AC XY: 428 AN XY: 134222

Gnomad AFR exome AF: 0.000803

Gnomad AMR exome AF: 0.000811

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00291

Gnomad FIN exome AF: 0.00332

Gnomad NFE exome AF: 0.00487

Gnomad OTH exome AF: 0.00279

GnomAD4 exome AF: 0.00393 AC: 5730 AN: 1459512 Hom.: 25 Cov.: 32 AF XY: 0.00394 AC XY: 2859 AN XY: 726194

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00300

Gnomad4 FIN exome AF: 0.00434

Gnomad4 NFE exome AF: 0.00445

Gnomad4 OTH exome AF: 0.00346

GnomAD4 genome AF: 0.00303 AC: 461 AN: 152320 Hom.: 4 Cov.: 32 AF XY: 0.00279 AC XY: 208 AN XY: 74480

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.00349

Gnomad4 NFE AF: 0.00528

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00433 Hom.: 4

Bravo AF: 0.00263

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00583

EpiControl AF: 0.00599

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:26

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:8

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 15, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	NF1: BP4, BP7, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 16, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 31, 2016	Variant summary: The NF1 c.5172G>A (p.Lys1724Lys) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. This variant was found in 408/119678 control chromosomes (1 homozygote), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0047796 (314/65696). This frequency is about 23 times the estimated maximal expected allele frequency of a pathogenic NF1 variant (0.0002084), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. This variant has been reported in nF1 patients with classification of benign. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 01, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Lys1745Lys in exon 37 of NF1: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 0.5% (42/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs17887014). -

Neurofibromatosis, type 1 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 26, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Neurofibromatosis, familial spinal Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 19, 2014	General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 27, 2020	- -

Neurofibromatosis-Noonan syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Café-au-lait macules with pulmonary stenosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	8.4
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs17887014; hg19: chr17-29653237; COSMIC: COSV55985986; COSMIC: COSV55985986;