17-31336607-T-TA

Position:

• chr17-31336607-T-TA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001042492.3(NF1):​c.6148-17dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 1,430,912 control chromosomes in the GnomAD database, including 22,083 homozygotes. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.34 (9278 hom., cov: 0)
  • Exomes 𝑓: 0.25 (12805 hom.)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.877

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 -16 ACMG points.

• BP6: Variant 17-31336607-T-TA is Benign according to our data. Variant chr17-31336607-T-TA is described in ClinVar as [Benign]. Clinvar id is 495785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.451 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.6148-17dupA		intron_variant		ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.6085-17dupA		intron_variant			NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.6148-17dupA		intron_variant		1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.342 AC: 51029 AN: 149214 Hom.: 9270 Cov.: 0

Gnomad AFR AF: 0.458

Gnomad AMI AF: 0.257

Gnomad AMR AF: 0.397

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.415

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.304

Gnomad MID AF: 0.164

Gnomad NFE AF: 0.277

Gnomad OTH AF: 0.297

GnomAD3 exomes AF: 0.255 AC: 35631 AN: 139834 Hom.: 1299 AF XY: 0.245 AC XY: 18603 AN XY: 75790

Gnomad AFR exome AF: 0.352

Gnomad AMR exome AF: 0.345

Gnomad ASJ exome AF: 0.176

Gnomad EAS exome AF: 0.313

Gnomad SAS exome AF: 0.205

Gnomad FIN exome AF: 0.259

Gnomad NFE exome AF: 0.228

Gnomad OTH exome AF: 0.236

GnomAD4 exome AF: 0.253 AC: 324037 AN: 1281614 Hom.: 12805 Cov.: 33 AF XY: 0.250 AC XY: 159018 AN XY: 635266

Gnomad4 AFR exome AF: 0.364

Gnomad4 AMR exome AF: 0.339

Gnomad4 ASJ exome AF: 0.181

Gnomad4 EAS exome AF: 0.344

Gnomad4 SAS exome AF: 0.204

Gnomad4 FIN exome AF: 0.272

Gnomad4 NFE exome AF: 0.249

Gnomad4 OTH exome AF: 0.251

GnomAD4 genome AF: 0.342 AC: 51058 AN: 149298 Hom.: 9278 Cov.: 0 AF XY: 0.345 AC XY: 25114 AN XY: 72804

Gnomad4 AFR AF: 0.457

Gnomad4 AMR AF: 0.397

Gnomad4 ASJ AF: 0.208

Gnomad4 EAS AF: 0.416

Gnomad4 SAS AF: 0.249

Gnomad4 FIN AF: 0.304

Gnomad4 NFE AF: 0.277

Gnomad4 OTH AF: 0.298

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 12, 2016	Variant summary: The NF1 c.6085-17dupA variant involves the alteration of an intronic nucleotide with 5/5 splice prediction tools calculating no significant effect on splicing, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 9674/35378 (758 homozygotes, 1/3, frequency: 0.2734468), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic NF1 variant of 1/4798 (0.0002084), suggesting this variant is likely a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 13, 2019	- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 07, 2020

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BranchPoint Hunter		5.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs33925668; hg19: chr17-29663625;