rs2269855

Variant names:

• chr17-31155860-G-A
• rs2269855
• NM_001042492.3:c.61-123G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-31155860-G-A
• chr17-31155860-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001042492.3(NF1):​c.61-123G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.661 in 1,102,578 control chromosomes in the GnomAD database, including 247,481 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (27088 hom., cov: 32)
  • Exomes 𝑓: 0.68 (220393 hom.)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.854
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 17-31155860-G-A is Benign according to our data. Variant chr17-31155860-G-A is described in ClinVar as Benign. ClinVar VariationId is 561463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.61-123G>A		intron_variant	Intron 1 of 57	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.61-123G>A		intron_variant	Intron 1 of 56		NP_000258.1
NF1	NM_001128147.3	c.61-123G>A		intron_variant	Intron 1 of 14		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.61-123G>A		intron_variant	Intron 1 of 57	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.570 AC: 86627 AN: 151860 Hom.: 27081 Cov.: 32

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.722

Gnomad AMR AF: 0.565

Gnomad ASJ AF: 0.768

Gnomad EAS AF: 0.562

Gnomad SAS AF: 0.621

Gnomad FIN AF: 0.656

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.704

Gnomad OTH AF: 0.628

GnomAD4 exome AF: 0.676 AC: 642426 AN: 950600 Hom.: 220393 AF XY: 0.676 AC XY: 327996 AN XY: 485216

African (AFR) AF: 0.294 AC: 6234 AN: 21176

American (AMR) AF: 0.523 AC: 14749 AN: 28218

Ashkenazi Jewish (ASJ) AF: 0.775 AC: 16616 AN: 21432

East Asian (EAS) AF: 0.557 AC: 18683 AN: 33560

South Asian (SAS) AF: 0.633 AC: 40698 AN: 64268

European-Finnish (FIN) AF: 0.653 AC: 26696 AN: 40868

Middle Eastern (MID) AF: 0.760 AC: 2479 AN: 3260

European-Non Finnish (NFE) AF: 0.702 AC: 487483 AN: 694794

Other (OTH) AF: 0.669 AC: 28788 AN: 43024

GnomAD4 genome AF: 0.570 AC: 86667 AN: 151978 Hom.: 27088 Cov.: 32 AF XY: 0.567 AC XY: 42123 AN XY: 74298

African (AFR) AF: 0.303 AC: 12561 AN: 41444

American (AMR) AF: 0.564 AC: 8611 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.768 AC: 2667 AN: 3472

East Asian (EAS) AF: 0.561 AC: 2906 AN: 5176

South Asian (SAS) AF: 0.620 AC: 2990 AN: 4822

European-Finnish (FIN) AF: 0.656 AC: 6915 AN: 10538

Middle Eastern (MID) AF: 0.772 AC: 227 AN: 294

European-Non Finnish (NFE) AF: 0.704 AC: 47809 AN: 67956

Other (OTH) AF: 0.629 AC: 1325 AN: 2108

Alfa AF: 0.596 Hom.: 4397

Bravo AF: 0.553

Asia WGS AF: 0.577 AC: 2006 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 20, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.0
DANN	Benign	0.72
PhyloP100		0.85
Mutation Taster		=97/3	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: rs2269855; hg19: chr17-29482878; COSMIC: COSV62206109; COSMIC: COSV62206109;