rs964288

Positions:

• chr17-31352228-G-A
• chr17-31352228-G-C

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.7458-29G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 1,604,790 control chromosomes in the GnomAD database, including 278,373 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.50 (20795 hom., cov: 30)
  • Exomes 𝑓: 0.59 (257578 hom.)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.23

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: This place is a probable branch point but likely benign (scored 2 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 17-31352228-G-A is Benign according to our data. Variant chr17-31352228-G-A is described in ClinVar as [Benign]. Clinvar id is 257303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31352228-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.615 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.7458-29G>A		intron_variant		ENST00000358273.9
NF1	NM_000267.3	c.7395-29G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.7458-29G>A		intron_variant		1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes AF: 0.501 AC: 75980 AN: 151750 Hom.: 20787 Cov.: 30

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.677

Gnomad AMR AF: 0.446

Gnomad ASJ AF: 0.684

Gnomad EAS AF: 0.356

Gnomad SAS AF: 0.568

Gnomad FIN AF: 0.600

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.620

Gnomad OTH AF: 0.532

GnomAD3 exomes AF: 0.535 AC: 133828 AN: 250220 Hom.: 37746 AF XY: 0.552 AC XY: 74658 AN XY: 135286

Gnomad AFR exome AF: 0.276

Gnomad AMR exome AF: 0.376

Gnomad ASJ exome AF: 0.686

Gnomad EAS exome AF: 0.354

Gnomad SAS exome AF: 0.576

Gnomad FIN exome AF: 0.600

Gnomad NFE exome AF: 0.611

Gnomad OTH exome AF: 0.568

GnomAD4 exome AF: 0.589 AC: 856432 AN: 1452922 Hom.: 257578 Cov.: 28 AF XY: 0.591 AC XY: 427847 AN XY: 723354

Gnomad4 AFR exome AF: 0.272

Gnomad4 AMR exome AF: 0.387

Gnomad4 ASJ exome AF: 0.688

Gnomad4 EAS exome AF: 0.374

Gnomad4 SAS exome AF: 0.579

Gnomad4 FIN exome AF: 0.596

Gnomad4 NFE exome AF: 0.614

Gnomad4 OTH exome AF: 0.573

GnomAD4 genome AF: 0.501 AC: 76013 AN: 151868 Hom.: 20795 Cov.: 30 AF XY: 0.498 AC XY: 36943 AN XY: 74210

Gnomad4 AFR AF: 0.287

Gnomad4 AMR AF: 0.445

Gnomad4 ASJ AF: 0.684

Gnomad4 EAS AF: 0.356

Gnomad4 SAS AF: 0.567

Gnomad4 FIN AF: 0.600

Gnomad4 NFE AF: 0.620

Gnomad4 OTH AF: 0.529

Alfa AF: 0.510 Hom.: 3467

Bravo AF: 0.478

Asia WGS AF: 0.441 AC: 1531 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 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	-	- -

Neurofibromatosis, type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

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	-0.76
CADD	Benign	17
DANN	Benign	0.55
BranchPoint Hunter		2.0

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: rs964288; hg19: chr17-29679246; COSMIC: COSV62205017; COSMIC: COSV62205017;