rs17880521

chr17-31325913-G-Achr17-31325913-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001042492.3(NF1):c.4929G>A(p.Val1643=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00457 in 1,614,072 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V1643V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.014 (43 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (43 hom.)
• Consequence: NF1 NM_001042492.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 2.17

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=-0.51).
• BP6: Variant 17-31325913-G-A is Benign according to our data. Variant chr17-31325913-G-A is described in ClinVar as [Benign]. Clinvar id is 184149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31325913-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.17 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0144 (2188/152250) while in subpopulation AFR AF= 0.0427 (1772/41526). AF 95% confidence interval is 0.041. There are 43 homozygotes in gnomad4. There are 1048 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 2185 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.4929G>A	p.Val1643=	synonymous_variant	37/58	ENST00000358273.9
NF1	NM_000267.3	c.4866G>A	p.Val1622=	synonymous_variant	36/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.4929G>A	p.Val1643=	synonymous_variant	37/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2185 AN: 152132 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.0427

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0133

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00209

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.00525 AC: 1319 AN: 251306 Hom.: 19 AF XY: 0.00439 AC XY: 596 AN XY: 135816

Gnomad AFR exome AF: 0.0443

Gnomad AMR exome AF: 0.00503

Gnomad ASJ exome AF: 0.00685

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00254

Gnomad OTH exome AF: 0.00783

GnomAD4 exome AF: 0.00355 AC: 5194 AN: 1461822 Hom.: 43 Cov.: 32 AF XY: 0.00340 AC XY: 2470 AN XY: 727204

Gnomad4 AFR exome AF: 0.0481

Gnomad4 AMR exome AF: 0.00581

Gnomad4 ASJ exome AF: 0.00727

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000742

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.00234

Gnomad4 OTH exome AF: 0.00633

GnomAD4 genome AF: 0.0144 AC: 2188 AN: 152250 Hom.: 43 Cov.: 32 AF XY: 0.0141 AC XY: 1048 AN XY: 74440

Gnomad4 AFR AF: 0.0427

Gnomad4 AMR AF: 0.0133

Gnomad4 ASJ AF: 0.00691

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00209

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0101 Hom.: 15

Bravo AF: 0.0172

Asia WGS AF: 0.00318 AC: 12 AN: 3478

EpiCase AF: 0.00371

EpiControl AF: 0.00296

ClinVar

Significance: Benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 20, 2014	p.Val1643Val in exon 37 of NF1: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 0.2% (21/8600) of Eu ropean American chromosomes and 4.3% (191/4406) of African American chromosomes by the NHLBI Exome sequencing project (http://evs.gs.washington.edu/EVS/; dbSNP rs17880521). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Neurofibromatosis, type 1 Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
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	Invitae	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. -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2016	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, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 13, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 30, 2016	Variant summary: The NF1 c.4866G>A (p.Val1622Val) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 3/5 splice prediction tools predict no significant impact on splicing. ESE finder predicts that this variant may affect ESE site of SC35. This variant was found in 687/121388 control chromosomes (11 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.0441346 (459/10400). This frequency is about 212 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 African origin. This variant has been reported in NF1 patients and RT-PCR showed no changes on transcripts; authors classified this variant as a polymorphism (Boulandet, 2000). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	NF1: BP4, BP7, BS1, BS2 -

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	curation	Sema4, Sema4	Mar 23, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 21, 2014	General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

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

Mar 21, 2015

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	6.8
Dann	Benign	0.76

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: rs17880521; hg19: chr17-29652931; COSMIC: COSV55986970; COSMIC: COSV55986970;