rs9894648

Positions:

• chr17-31326275-T-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.5268+23T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.621 in 1,599,250 control chromosomes in the GnomAD database, including 312,036 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32442 hom., cov: 32)
  • Exomes 𝑓: 0.62 (279594 hom.)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.00900

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=-0.83).
• BP6: Variant 17-31326275-T-C is Benign according to our data. Variant chr17-31326275-T-C is described in ClinVar as [Benign]. Clinvar id is 257293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31326275-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.742 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.5268+23T>C		intron_variant		ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.5205+23T>C		intron_variant			NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.5268+23T>C		intron_variant		1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.647 AC: 98310 AN: 151888 Hom.: 32416 Cov.: 32

Gnomad AFR AF: 0.749

Gnomad AMI AF: 0.697

Gnomad AMR AF: 0.510

Gnomad ASJ AF: 0.704

Gnomad EAS AF: 0.447

Gnomad SAS AF: 0.620

Gnomad FIN AF: 0.620

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.634

Gnomad OTH AF: 0.651

GnomAD3 exomes AF: 0.591 AC: 140307 AN: 237330 Hom.: 42754 AF XY: 0.601 AC XY: 77761 AN XY: 129426

Gnomad AFR exome AF: 0.753

Gnomad AMR exome AF: 0.413

Gnomad ASJ exome AF: 0.704

Gnomad EAS exome AF: 0.441

Gnomad SAS exome AF: 0.625

Gnomad FIN exome AF: 0.618

Gnomad NFE exome AF: 0.625

Gnomad OTH exome AF: 0.608

GnomAD4 exome AF: 0.619 AC: 895405 AN: 1447244 Hom.: 279594 Cov.: 33 AF XY: 0.620 AC XY: 446658 AN XY: 720492

Gnomad4 AFR exome AF: 0.759

Gnomad4 AMR exome AF: 0.427

Gnomad4 ASJ exome AF: 0.706

Gnomad4 EAS exome AF: 0.473

Gnomad4 SAS exome AF: 0.628

Gnomad4 FIN exome AF: 0.610

Gnomad4 NFE exome AF: 0.624

Gnomad4 OTH exome AF: 0.623

GnomAD4 genome AF: 0.647 AC: 98373 AN: 152006 Hom.: 32442 Cov.: 32 AF XY: 0.642 AC XY: 47685 AN XY: 74270

Gnomad4 AFR AF: 0.749

Gnomad4 AMR AF: 0.510

Gnomad4 ASJ AF: 0.704

Gnomad4 EAS AF: 0.446

Gnomad4 SAS AF: 0.618

Gnomad4 FIN AF: 0.620

Gnomad4 NFE AF: 0.634

Gnomad4 OTH AF: 0.647

Alfa AF: 0.643 Hom.: 5860

Bravo AF: 0.643

Asia WGS AF: 0.527 AC: 1831 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

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	- -

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	-0.83
CADD	Benign	2.3
DANN	Benign	0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs9894648; hg19: chr17-29653293; COSMIC: COSV55985627; COSMIC: COSV55985627;