rs1800845

Variant names:

• chr17-31376420-C-G
• rs1800845
• NM_001042492.3:c.*2265C>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001042492.3(NF1):​c.*2265C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.442 in 232,422 control chromosomes in the GnomAD database, including 28,525 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (22203 hom., cov: 32)
  • Exomes 𝑓: 0.36 (6322 hom.)
• Consequence: NF1 NM_001042492.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.897

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 17-31376420-C-G is Benign according to our data. Variant chr17-31376420-C-G is described in ClinVar as [Benign]. Clinvar id is 322599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31376420-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.85 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.*2265C>G		3_prime_UTR_variant	Exon 58 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.*2265C>G		3_prime_UTR_variant	Exon 57 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.*2265C>G		3_prime_UTR_variant	Exon 58 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.482 AC: 73298 AN: 151956 Hom.: 22137 Cov.: 32

Gnomad AFR AF: 0.857

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.537

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.345

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.299

Gnomad OTH AF: 0.410

GnomAD4 exome AF: 0.364 AC: 29243 AN: 80348 Hom.: 6322 Cov.: 0 AF XY: 0.358 AC XY: 13214 AN XY: 36936

Gnomad4 AFR exome AF: 0.856

Gnomad4 AMR exome AF: 0.481

Gnomad4 ASJ exome AF: 0.235

Gnomad4 EAS exome AF: 0.559

Gnomad4 SAS exome AF: 0.384

Gnomad4 FIN exome AF: 0.276

Gnomad4 NFE exome AF: 0.289

Gnomad4 OTH exome AF: 0.371

GnomAD4 genome AF: 0.483 AC: 73430 AN: 152074 Hom.: 22203 Cov.: 32 AF XY: 0.486 AC XY: 36112 AN XY: 74328

Gnomad4 AFR AF: 0.858

Gnomad4 AMR AF: 0.470

Gnomad4 ASJ AF: 0.237

Gnomad4 EAS AF: 0.537

Gnomad4 SAS AF: 0.387

Gnomad4 FIN AF: 0.345

Gnomad4 NFE AF: 0.299

Gnomad4 OTH AF: 0.409

Alfa AF: 0.410 Hom.: 2054

Bravo AF: 0.506

Asia WGS AF: 0.486 AC: 1691 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Neurofibromatosis, familial spinal Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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-Noonan syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.7
DANN	Benign	0.63

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: rs1800845; hg19: chr17-29703438;