rs2953000

Positions:

• chr17-31182773-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001042492.3(NF1):​c.888+108C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.645 in 1,034,132 control chromosomes in the GnomAD database, including 223,672 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.55 (26002 hom., cov: 33)
  • Exomes 𝑓: 0.66 (197670 hom.)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.209

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 17-31182773-C-T is Benign according to our data. Variant chr17-31182773-C-T is described in ClinVar as [Benign]. Clinvar id is 561465.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.888+108C>T		intron_variant		ENST00000358273.9
NF1	NM_000267.3	c.888+108C>T		intron_variant
NF1	NM_001128147.3	c.888+108C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.888+108C>T		intron_variant		1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes AF: 0.552 AC: 83639 AN: 151540 Hom.: 26005 Cov.: 33

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.719

Gnomad AMR AF: 0.558

Gnomad ASJ AF: 0.765

Gnomad EAS AF: 0.473

Gnomad SAS AF: 0.617

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.772

Gnomad NFE AF: 0.703

Gnomad OTH AF: 0.616

GnomAD4 exome AF: 0.661 AC: 583581 AN: 882474 Hom.: 197670 Cov.: 11 AF XY: 0.663 AC XY: 301109 AN XY: 454342

Gnomad4 AFR exome AF: 0.239

Gnomad4 AMR exome AF: 0.517

Gnomad4 ASJ exome AF: 0.772

Gnomad4 EAS exome AF: 0.458

Gnomad4 SAS exome AF: 0.631

Gnomad4 FIN exome AF: 0.654

Gnomad4 NFE exome AF: 0.695

Gnomad4 OTH exome AF: 0.655

GnomAD4 genome AF: 0.552 AC: 83643 AN: 151658 Hom.: 26002 Cov.: 33 AF XY: 0.547 AC XY: 40573 AN XY: 74106

Gnomad4 AFR AF: 0.252

Gnomad4 AMR AF: 0.557

Gnomad4 ASJ AF: 0.765

Gnomad4 EAS AF: 0.473

Gnomad4 SAS AF: 0.616

Gnomad4 FIN AF: 0.653

Gnomad4 NFE AF: 0.703

Gnomad4 OTH AF: 0.616

Alfa AF: 0.597 Hom.: 4295

Bravo AF: 0.533

Asia WGS AF: 0.530 AC: 1842 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.6
DANN	Benign	0.59

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: rs2953000; hg19: chr17-29509791; COSMIC: COSV62206118;