rs2066736

chr17-31232914-C-Achr17-31232914-C-Gchr17-31232914-C-T

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.3496+33C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,612,700 control chromosomes in the GnomAD database, including 93,276 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13872 hom., cov: 31)
  • Exomes 𝑓: 0.32 (79404 hom.)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.204

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=-0.86).
• BP6: Variant 17-31232914-C-A is Benign according to our data. Variant chr17-31232914-C-A is described in ClinVar as [Benign]. Clinvar id is 257285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31232914-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.605 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.3496+33C>A		intron_variant		ENST00000358273.9
NF1	NM_000267.3	c.3496+33C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.3496+33C>A		intron_variant		1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes AF: 0.404 AC: 61271 AN: 151822 Hom.: 13847 Cov.: 31

Gnomad AFR AF: 0.611

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.426

Gnomad ASJ AF: 0.232

Gnomad EAS AF: 0.438

Gnomad SAS AF: 0.372

Gnomad FIN AF: 0.344

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.294

Gnomad OTH AF: 0.344

GnomAD3 exomes AF: 0.365 AC: 91091 AN: 249686 Hom.: 17902 AF XY: 0.351 AC XY: 47444 AN XY: 135018

Gnomad AFR exome AF: 0.616

Gnomad AMR exome AF: 0.486

Gnomad ASJ exome AF: 0.223

Gnomad EAS exome AF: 0.437

Gnomad SAS exome AF: 0.365

Gnomad FIN exome AF: 0.340

Gnomad NFE exome AF: 0.300

Gnomad OTH exome AF: 0.324

GnomAD4 exome AF: 0.322 AC: 469868 AN: 1460760 Hom.: 79404 Cov.: 34 AF XY: 0.321 AC XY: 233103 AN XY: 726724

Gnomad4 AFR exome AF: 0.622

Gnomad4 AMR exome AF: 0.477

Gnomad4 ASJ exome AF: 0.225

Gnomad4 EAS exome AF: 0.444

Gnomad4 SAS exome AF: 0.363

Gnomad4 FIN exome AF: 0.344

Gnomad4 NFE exome AF: 0.300

Gnomad4 OTH exome AF: 0.324

GnomAD4 genome AF: 0.404 AC: 61346 AN: 151940 Hom.: 13872 Cov.: 31 AF XY: 0.408 AC XY: 30275 AN XY: 74266

Gnomad4 AFR AF: 0.611

Gnomad4 AMR AF: 0.426

Gnomad4 ASJ AF: 0.232

Gnomad4 EAS AF: 0.439

Gnomad4 SAS AF: 0.374

Gnomad4 FIN AF: 0.344

Gnomad4 NFE AF: 0.294

Gnomad4 OTH AF: 0.343

Alfa AF: 0.252 Hom.: 920

Bravo AF: 0.417

Asia WGS AF: 0.416 AC: 1448 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 10, 2018	- -

Neurofibromatosis, type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2018

- -

Neurofibromatosis, familial spinal Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	1.0
Dann	Benign	0.61

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: rs2066736; hg19: chr17-29559932; COSMIC: COSV62196981; COSMIC: COSV62196981;