17-31232043-ATTTTTTTTTTTTTTT-ATTTTTTTTTTTT

Position:

• chr17-31232043-ATTTTTTTTTTTTTTT-ATTTTTTTTTTTT

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001042492.3(NF1):​c.3198-6_3198-4delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00362 in 587,606 control chromosomes in the GnomAD database, including 7 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0076 (6 hom., cov: 0)
  • Exomes 𝑓: 0.0029 (1 hom.)
• Consequence: NF1 NM_001042492.3 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.96

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 -10 ACMG points.

• BP6: Variant 17-31232043-ATTT-A is Benign according to our data. Variant chr17-31232043-ATTT-A is described in ClinVar as [Likely_benign]. Clinvar id is 1199777.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-31232043-ATTT-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00757 (688/90874) while in subpopulation AFR AF= 0.0294 (660/22432). AF 95% confidence interval is 0.0276. There are 6 homozygotes in gnomad4. There are 312 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 688 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.3198-6_3198-4delTTT		splice_region_variant, intron_variant		ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.3198-6_3198-4delTTT		splice_region_variant, intron_variant			NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.3198-6_3198-4delTTT		splice_region_variant, intron_variant		1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.00758 AC: 689 AN: 90878 Hom.: 6 Cov.: 0

Gnomad AFR AF: 0.0295

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00256

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000209

Gnomad OTH AF: 0.00656

GnomAD4 exome AF: 0.00290 AC: 1441 AN: 496732 Hom.: 1 AF XY: 0.00289 AC XY: 755 AN XY: 261118

Gnomad4 AFR exome AF: 0.0209

Gnomad4 AMR exome AF: 0.00389

Gnomad4 ASJ exome AF: 0.00543

Gnomad4 EAS exome AF: 0.00473

Gnomad4 SAS exome AF: 0.00169

Gnomad4 FIN exome AF: 0.00257

Gnomad4 NFE exome AF: 0.00227

Gnomad4 OTH exome AF: 0.00396

GnomAD4 genome AF: 0.00757 AC: 688 AN: 90874 Hom.: 6 Cov.: 0 AF XY: 0.00742 AC XY: 312 AN XY: 42028

Gnomad4 AFR AF: 0.0294

Gnomad4 AMR AF: 0.00256

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000209

Gnomad4 OTH AF: 0.00653

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

NF1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 13, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 30, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs371047262; hg19: chr17-29559061;