rs138840528

Positions:

• chr17-31182623-G-A
• chr17-31182623-G-C

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.846G>A​(p.Gln282=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00366 in 1,613,864 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (89 hom.)
• Consequence: NF1 NM_001042492.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 0.844

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=-0.47).
• BP6: Variant 17-31182623-G-A is Benign according to our data. Variant chr17-31182623-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 184123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31182623-G-A is described in Lovd as [Benign]. Variant chr17-31182623-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.844 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00236 (359/152298) while in subpopulation SAS AF= 0.0286 (138/4824). AF 95% confidence interval is 0.0247. There are 1 homozygotes in gnomad4. There are 209 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 359 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.846G>A	p.Gln282=	synonymous_variant	8/58	ENST00000358273.9
NF1	NM_000267.3	c.846G>A	p.Gln282=	synonymous_variant	8/57
NF1	NM_001128147.3	c.846G>A	p.Gln282=	synonymous_variant	8/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.846G>A	p.Gln282=	synonymous_variant	8/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 360 AN: 152182 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0288

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00210

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00548 AC: 1374 AN: 250938 Hom.: 29 AF XY: 0.00700 AC XY: 949 AN XY: 135620

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.000782

Gnomad ASJ exome AF: 0.00884

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0324

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.00196

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00379 AC: 5543 AN: 1461566 Hom.: 89 Cov.: 32 AF XY: 0.00482 AC XY: 3507 AN XY: 727068

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.000805

Gnomad4 ASJ exome AF: 0.00903

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0329

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.00184

Gnomad4 OTH exome AF: 0.00462

GnomAD4 genome AF: 0.00236 AC: 359 AN: 152298 Hom.: 1 Cov.: 32 AF XY: 0.00281 AC XY: 209 AN XY: 74478

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0286

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00210

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00245 Hom.: 1

Bravo AF: 0.00164

Asia WGS AF: 0.0120 AC: 41 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:22

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:7

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2017	Variant summary: The NF1 c.846G>A (p.Gln282Gln) 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. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant does not affect any ESE site. This variant was found in 706/116664 control chromosomes (23 homozygotes) at a frequency of 0.0060516, which is approximately 29 times the estimated maximal expected allele frequency of a pathogenic NF1 variant (0.0002084), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 01, 2019	This variant is associated with the following publications: (PMID: 12552569, 26979654, 15146469, 15060124, 15994866, 15863657, 16944272, 27182040, 17726231, 27535533, 28536309) -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	Oct 08, 2015	p.Gln282Gln in exon 8 of NF1: This variant is not expected to have clinical sign ificance because it has been identified in 3.43% (542/15784) of South Asian chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs138840528). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Neurofibromatosis, type 1 Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 26, 2020	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -

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. -

Myopathy, centronuclear, 5 Benign:1

Benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

-

The heterozygous c.846G>A (p.Gln282=) variant in NF1 has been identified in an individual with neurofibromatosis (PMID: 15060124), and has been identified in >3% of South Asian chromosomes and 23 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal dominant neurofibromatosis. -

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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2019

This alteration is classified as likely 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. -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 16, 2014

This alteration is classified as likely 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	-0.47
CADD	Benign	6.5
DANN	Benign	0.68

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: rs138840528; hg19: chr17-29509641; COSMIC: COSV62201020;