17-31218969-AT-ATT

Variant names:

• chr17-31218969-A-AT
• rs398119783
• NM_001042492.3:c.1528-29dupT

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.1528-29dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.662 in 1,531,434 control chromosomes in the GnomAD database, including 342,313 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (27459 hom., cov: 0)
  • Exomes 𝑓: 0.67 (314854 hom.)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.685
• Publications: 1 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 17-31218969-A-AT is Benign according to our data. Variant chr17-31218969-A-AT is described in ClinVar as Benign. ClinVar VariationId is 257277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.1528-29dupT		intron_variant	Intron 13 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.1528-29dupT		intron_variant	Intron 13 of 56		NP_000258.1
NF1	NM_001128147.3	c.1528-29dupT		intron_variant	Intron 13 of 14		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.1528-36_1528-35insT		intron_variant	Intron 13 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.578 AC: 87645 AN: 151654 Hom.: 27452 Cov.: 0

Gnomad AFR AF: 0.325

Gnomad AMI AF: 0.719

Gnomad AMR AF: 0.568

Gnomad ASJ AF: 0.768

Gnomad EAS AF: 0.562

Gnomad SAS AF: 0.622

Gnomad FIN AF: 0.657

Gnomad MID AF: 0.797

Gnomad NFE AF: 0.705

Gnomad OTH AF: 0.638

GnomAD2 exomes AF: 0.626 AC: 120735 AN: 192966 AF XY: 0.638

Gnomad AFR exome AF: 0.316

Gnomad AMR exome AF: 0.509

Gnomad ASJ exome AF: 0.777

Gnomad EAS exome AF: 0.560

Gnomad FIN exome AF: 0.660

Gnomad NFE exome AF: 0.694

Gnomad OTH exome AF: 0.675

GnomAD4 exome AF: 0.671 AC: 926025 AN: 1379662 Hom.: 314854 Cov.: 29 AF XY: 0.672 AC XY: 460726 AN XY: 685188

African (AFR) AF: 0.311 AC: 9797 AN: 31508

American (AMR) AF: 0.517 AC: 20968 AN: 40584

Ashkenazi Jewish (ASJ) AF: 0.773 AC: 19446 AN: 25162

East Asian (EAS) AF: 0.552 AC: 20581 AN: 37254

South Asian (SAS) AF: 0.631 AC: 51201 AN: 81086

European-Finnish (FIN) AF: 0.655 AC: 33161 AN: 50656

Middle Eastern (MID) AF: 0.772 AC: 4346 AN: 5626

European-Non Finnish (NFE) AF: 0.693 AC: 728461 AN: 1050578

Other (OTH) AF: 0.665 AC: 38064 AN: 57208

GnomAD4 genome AF: 0.578 AC: 87686 AN: 151772 Hom.: 27459 Cov.: 0 AF XY: 0.574 AC XY: 42552 AN XY: 74168

African (AFR) AF: 0.326 AC: 13476 AN: 41332

American (AMR) AF: 0.568 AC: 8663 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.768 AC: 2664 AN: 3470

East Asian (EAS) AF: 0.561 AC: 2894 AN: 5160

South Asian (SAS) AF: 0.620 AC: 2986 AN: 4814

European-Finnish (FIN) AF: 0.657 AC: 6896 AN: 10496

Middle Eastern (MID) AF: 0.796 AC: 234 AN: 294

European-Non Finnish (NFE) AF: 0.705 AC: 47875 AN: 67940

Other (OTH) AF: 0.638 AC: 1347 AN: 2110

Alfa AF: 0.604 Hom.: 3783

Bravo AF: 0.559

Asia WGS AF: 0.579 AC: 2014 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.69
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs398119783; hg19: chr17-29545987;