rs1801052

Positions:

• chr17-31181757-G-A
• chr17-31181757-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001042492.3(NF1):​c.702G>A​(p.Leu234Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.665 in 1,604,776 control chromosomes in the GnomAD database, including 363,710 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (26997 hom., cov: 29)
  • Exomes 𝑓: 0.68 (336713 hom.)
• Consequence: NF1 NM_001042492.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: -1.86

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 17-31181757-G-A is Benign according to our data. Variant chr17-31181757-G-A is described in ClinVar as [Benign]. Clinvar id is 183825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31181757-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.86 with no splicing effect.
• 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/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.702G>A	p.Leu234Leu	synonymous_variant	7/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.702G>A	p.Leu234Leu	synonymous_variant	7/57		NP_000258.1
NF1	NM_001128147.3	c.702G>A	p.Leu234Leu	synonymous_variant	7/15		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.702G>A	p.Leu234Leu	synonymous_variant	7/58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.572 AC: 86258 AN: 150814 Hom.: 26990 Cov.: 29

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.720

Gnomad AMR AF: 0.565

Gnomad ASJ AF: 0.768

Gnomad EAS AF: 0.562

Gnomad SAS AF: 0.627

Gnomad FIN AF: 0.660

Gnomad MID AF: 0.779

Gnomad NFE AF: 0.704

Gnomad OTH AF: 0.631

GnomAD3 exomes AF: 0.627 AC: 157498 AN: 251116 Hom.: 51250 AF XY: 0.643 AC XY: 87246 AN XY: 135778

Gnomad AFR exome AF: 0.290

Gnomad AMR exome AF: 0.507

Gnomad ASJ exome AF: 0.776

Gnomad EAS exome AF: 0.561

Gnomad SAS exome AF: 0.635

Gnomad FIN exome AF: 0.662

Gnomad NFE exome AF: 0.698

Gnomad OTH exome AF: 0.671

GnomAD4 exome AF: 0.675 AC: 981504 AN: 1453854 Hom.: 336713 Cov.: 37 AF XY: 0.676 AC XY: 489500 AN XY: 723658

Gnomad4 AFR exome AF: 0.286

Gnomad4 AMR exome AF: 0.516

Gnomad4 ASJ exome AF: 0.775

Gnomad4 EAS exome AF: 0.555

Gnomad4 SAS exome AF: 0.637

Gnomad4 FIN exome AF: 0.657

Gnomad4 NFE exome AF: 0.699

Gnomad4 OTH exome AF: 0.669

GnomAD4 genome AF: 0.572 AC: 86299 AN: 150922 Hom.: 26997 Cov.: 29 AF XY: 0.568 AC XY: 41858 AN XY: 73630

Gnomad4 AFR AF: 0.304

Gnomad4 AMR AF: 0.565

Gnomad4 ASJ AF: 0.768

Gnomad4 EAS AF: 0.562

Gnomad4 SAS AF: 0.626

Gnomad4 FIN AF: 0.660

Gnomad4 NFE AF: 0.704

Gnomad4 OTH AF: 0.632

Alfa AF: 0.679 Hom.: 50180

Bravo AF: 0.554

Asia WGS AF: 0.578 AC: 2007 AN: 3472

EpiCase AF: 0.720

EpiControl AF: 0.721

ClinVar

Significance: Benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 02, 2014	This is a RefSeq error. The reference base (c.702G) is the minor allele. The c.7 02A allele has been identified in 70% (46585/66678) of European chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org, dbSNP rs1 801052) and thus meets criteria to be classified as benign. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2015	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Neurofibromatosis, type 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 11, 2016	Variant summary: The NF1 c.702G>A (p.Leu234Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant and 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 75516/121252 control chromosomes (24613 homozygotes) at a frequency of 0.6228021, signifying it is the common allele in the population and is thus a benign polymorphism. In addition, one clinical diagnostic laboratories has classified this variant as benign. Taken together, this variant is classified as benign. -

Neurofibromatosis, familial spinal Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 17, 2014	This alteration is classified as benign based on a combination of the following: 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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 09, 2019	- -

Neurofibromatosis-Noonan syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2014

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	-0.83
CADD	Benign	0.042
DANN	Benign	0.65

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: rs1801052; hg19: chr17-29508775; COSMIC: COSV62193259;