17-31352383-A-G

Position:

• chr17-31352383-A-G

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.7584A>G​(p.Gln2528=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000978 in 1,614,034 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00095 (5 hom.)
• Consequence: NF1 NM_001042492.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:15
• Conservation: PhyloP100: 3.15

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 17-31352383-A-G is Benign according to our data. Variant chr17-31352383-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 184154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31352383-A-G is described in Lovd as [Benign]. Variant chr17-31352383-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=3.15 with no splicing effect.
• BS2: High AC in GnomAd4 at 195 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.7584A>G	p.Gln2528=	synonymous_variant	51/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.7521A>G	p.Gln2507=	synonymous_variant	50/57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.7584A>G	p.Gln2528=	synonymous_variant	51/58	1	NM_001042492.3	ENSP00000351015	P1

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 195 AN: 152178 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00113 AC: 284 AN: 251324 Hom.: 0 AF XY: 0.00107 AC XY: 145 AN XY: 135830

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00705

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000968

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.000946 AC: 1383 AN: 1461738 Hom.: 5 Cov.: 32 AF XY: 0.000956 AC XY: 695 AN XY: 727188

Gnomad4 AFR exome AF: 0.000956

Gnomad4 AMR exome AF: 0.00228

Gnomad4 ASJ exome AF: 0.00677

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000798

Gnomad4 OTH exome AF: 0.00227

GnomAD4 genome AF: 0.00128 AC: 195 AN: 152296 Hom.: 1 Cov.: 32 AF XY: 0.00136 AC XY: 101 AN XY: 74466

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.00445

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00113

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00123 Hom.: 0

Bravo AF: 0.00182

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00142

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Uncertain:1 Benign:4

Likely 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	Genome-Nilou Lab	Mar 15, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Medical Genetics, University of Parma	Feb 02, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 13, 2015	p.Gln2528Gln in exon 51 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 0.13% (83/66330) o f European American chromosomes by the Exome Aggregation Consortium (ExAC, http: //exac.broadinstitute.org; dbSNP rs55865524). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 22, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 07, 2021	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2021	This variant is associated with the following publications: (PMID: 31573083, 27534895) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	NF1: BP4, BS1 -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 13, 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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 12, 2021	- -

NF1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 07, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Neurofibromatosis, type 1;C0349639:Juvenile myelomonocytic leukemia;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	7.0
DANN	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs55865524; hg19: chr17-29679401; COSMIC: COSV62204673; COSMIC: COSV62204673;