17-31336607-TAA-TAAA

Variant names:

• chr17-31336607-T-TA
• rs33925668
• NM_001042492.3:c.6148-17dupA

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• neurofibromatosis type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
• Moyamoya disease

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042492.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	NM_001042492.3	MANE Select	c.6148-17dupA		intron	N/A	NP_001035957.1
	NF1	NM_000267.4		c.6085-17dupA		intron	N/A	NP_000258.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.6148-28_6148-27insA		intron	N/A	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.6085-28_6085-27insA		intron	N/A	ENSP00000348498.3
	NF1	ENST00000579081.6	TSL:1	n.*1313-28_*1313-27insA		intron	N/A	ENSP00000462408.2

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

GnomAD2 exomes AF: 0.255 AC: 35631 AN: 139834 AF XY: 0.245

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.364 AC: 9961 AN: 27352

American (AMR) AF: 0.339 AC: 9579 AN: 28250

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 4155 AN: 23004

East Asian (EAS) AF: 0.344 AC: 11974 AN: 34832

South Asian (SAS) AF: 0.204 AC: 14638 AN: 71796

European-Finnish (FIN) AF: 0.272 AC: 12389 AN: 45536

Middle Eastern (MID) AF: 0.145 AC: 654 AN: 4510

European-Non Finnish (NFE) AF: 0.249 AC: 247360 AN: 993202

Other (OTH) AF: 0.251 AC: 13327 AN: 53132

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.457 AC: 18523 AN: 40542

American (AMR) AF: 0.397 AC: 5945 AN: 14980

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 720 AN: 3460

East Asian (EAS) AF: 0.416 AC: 2124 AN: 5106

South Asian (SAS) AF: 0.249 AC: 1180 AN: 4746

European-Finnish (FIN) AF: 0.304 AC: 2970 AN: 9774

Middle Eastern (MID) AF: 0.165 AC: 47 AN: 284

European-Non Finnish (NFE) AF: 0.277 AC: 18702 AN: 67436

Other (OTH) AF: 0.298 AC: 615 AN: 2066

Alfa AF: 0.142 Hom.: 293

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 13, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 12, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

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

Jul 07, 2020

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.88
BranchPoint Hunter		5.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs33925668; hg19: chr17-29663625; COSMIC: COSV62205868; COSMIC: COSV62205868;