rs17883614

Positions:

• chr17-31337627-T-A

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.6642+45T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0337 in 1,555,824 control chromosomes in the GnomAD database, including 5,974 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (3032 hom., cov: 32)
  • Exomes 𝑓: 0.024 (2942 hom.)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.98

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]

NF1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 17-31337627-T-A is Benign according to our data. Variant chr17-31337627-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 257297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.6642+45T>A		intron_variant		ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.6579+45T>A		intron_variant			NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.6642+45T>A		intron_variant		1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.121 AC: 18332 AN: 152076 Hom.: 3025 Cov.: 32

Gnomad AFR AF: 0.375

Gnomad AMI AF: 0.0198

Gnomad AMR AF: 0.0559

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.0887

Gnomad SAS AF: 0.0496

Gnomad FIN AF: 0.0161

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0120

Gnomad OTH AF: 0.0986

GnomAD3 exomes AF: 0.0470 AC: 10963 AN: 233198 Hom.: 1178 AF XY: 0.0428 AC XY: 5449 AN XY: 127256

Gnomad AFR exome AF: 0.386

Gnomad AMR exome AF: 0.0287

Gnomad ASJ exome AF: 0.0170

Gnomad EAS exome AF: 0.0848

Gnomad SAS exome AF: 0.0465

Gnomad FIN exome AF: 0.0152

Gnomad NFE exome AF: 0.0116

Gnomad OTH exome AF: 0.0336

GnomAD4 exome AF: 0.0243 AC: 34071 AN: 1403630 Hom.: 2942 Cov.: 25 AF XY: 0.0242 AC XY: 16944 AN XY: 700742

Gnomad4 AFR exome AF: 0.389

Gnomad4 AMR exome AF: 0.0318

Gnomad4 ASJ exome AF: 0.0180

Gnomad4 EAS exome AF: 0.0987

Gnomad4 SAS exome AF: 0.0470

Gnomad4 FIN exome AF: 0.0138

Gnomad4 NFE exome AF: 0.00844

Gnomad4 OTH exome AF: 0.0417

GnomAD4 genome AF: 0.121 AC: 18355 AN: 152194 Hom.: 3032 Cov.: 32 AF XY: 0.119 AC XY: 8866 AN XY: 74416

Gnomad4 AFR AF: 0.374

Gnomad4 AMR AF: 0.0558

Gnomad4 ASJ AF: 0.0202

Gnomad4 EAS AF: 0.0878

Gnomad4 SAS AF: 0.0495

Gnomad4 FIN AF: 0.0161

Gnomad4 NFE AF: 0.0120

Gnomad4 OTH AF: 0.0975

Alfa AF: 0.0618 Hom.: 240

Bravo AF: 0.135

Asia WGS AF: 0.0800 AC: 279 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 2022	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -

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	-0.96
CADD	Benign	0.11
DANN	Benign	0.16

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: rs17883614; hg19: chr17-29664645; COSMIC: COSV104420394; COSMIC: COSV104420394;