17-31095288-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001042492.3(NF1):c.-22G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00598 in 1,534,806 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0062 (33 hom.)
• Consequence: NF1 NM_001042492.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.40

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]

MIR4733HG (HGNC:55332): (MIR4733 host gene)

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 17-31095288-G-C is Benign according to our data. Variant chr17-31095288-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 257274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31095288-G-C is described in Lovd as [Benign].
• BS2: High AC in GnomAd at 583 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.-22G>C		5_prime_UTR_variant	1/58	ENST00000358273.9
NF1	NM_000267.3	c.-22G>C		5_prime_UTR_variant	1/57
NF1	NM_001128147.3	c.-22G>C		5_prime_UTR_variant	1/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.-22G>C		5_prime_UTR_variant	1/58	1	NM_001042492.3	P1
MIR4733HG	ENST00000583377.1	n.163C>G		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes AF: 0.00384 AC: 583 AN: 151754 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00347

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00396

Gnomad FIN AF: 0.00633

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00596

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00383 AC: 502 AN: 131034 Hom.: 4 AF XY: 0.00408 AC XY: 292 AN XY: 71526

Gnomad AFR exome AF: 0.000622

Gnomad AMR exome AF: 0.00164

Gnomad ASJ exome AF: 0.00186

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00324

Gnomad FIN exome AF: 0.00643

Gnomad NFE exome AF: 0.00631

Gnomad OTH exome AF: 0.00547

GnomAD4 exome AF: 0.00622 AC: 8601 AN: 1382934 Hom.: 33 Cov.: 32 AF XY: 0.00626 AC XY: 4269 AN XY: 682374

Gnomad4 AFR exome AF: 0.000699

Gnomad4 AMR exome AF: 0.00163

Gnomad4 ASJ exome AF: 0.00195

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00334

Gnomad4 FIN exome AF: 0.00676

Gnomad4 NFE exome AF: 0.00710

Gnomad4 OTH exome AF: 0.00505

GnomAD4 genome AF: 0.00384 AC: 583 AN: 151872 Hom.: 1 Cov.: 30 AF XY: 0.00362 AC XY: 269 AN XY: 74230

Gnomad4 AFR AF: 0.00133

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00347

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00396

Gnomad4 FIN AF: 0.00633

Gnomad4 NFE AF: 0.00597

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00202 Hom.: 2

Bravo AF: 0.00358

Asia WGS AF: 0.000867 AC: 3 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 29, 2019	- -
Likely 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	- -

Neurofibromatosis, type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	NF1: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2018	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. -

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. -

Neurofibromatosis, familial spinal Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	19
Dann	Benign	0.90

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: rs556823296; hg19: chr17-29422306;