chr17-31327858-T-A

Variant names:

• chr17-31327858-T-A
• rs2285894
• NM_001042492.3:c.5609+19T>A

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.5609+19T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 1,605,644 control chromosomes in the GnomAD database, including 278,086 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (20825 hom., cov: 31)
  • Exomes 𝑓: 0.59 (257261 hom.)
• Consequence: NF1 NM_001042492.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.06
• Publications: 25 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=-0.89).
• BP6: Variant 17-31327858-T-A is Benign according to our data. Variant chr17-31327858-T-A is described in ClinVar as Benign. ClinVar VariationId is 257294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.614 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.5609+19T>A		intron	N/A	NP_001035957.1
	NF1	NM_000267.4		c.5546+19T>A		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.5609+19T>A		intron	N/A	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.5546+19T>A		intron	N/A	ENSP00000348498.3
	NF1	ENST00000579081.6	TSL:1	n.*774+19T>A		intron	N/A	ENSP00000462408.2

Frequencies

GnomAD3 genomes AF: 0.502 AC: 76225 AN: 151886 Hom.: 20816 Cov.: 31

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.678

Gnomad AMR AF: 0.446

Gnomad ASJ AF: 0.684

Gnomad EAS AF: 0.358

Gnomad SAS AF: 0.563

Gnomad FIN AF: 0.601

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.619

Gnomad OTH AF: 0.531

GnomAD2 exomes AF: 0.535 AC: 133633 AN: 249712 AF XY: 0.551

Gnomad AFR exome AF: 0.285

Gnomad AMR exome AF: 0.377

Gnomad ASJ exome AF: 0.686

Gnomad EAS exome AF: 0.356

Gnomad FIN exome AF: 0.600

Gnomad NFE exome AF: 0.611

Gnomad OTH exome AF: 0.567

GnomAD4 exome AF: 0.589 AC: 856724 AN: 1453640 Hom.: 257261 Cov.: 30 AF XY: 0.591 AC XY: 427869 AN XY: 723682

African (AFR) AF: 0.280 AC: 9304 AN: 33240

American (AMR) AF: 0.388 AC: 17326 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.687 AC: 17928 AN: 26102

East Asian (EAS) AF: 0.375 AC: 14862 AN: 39662

South Asian (SAS) AF: 0.576 AC: 49528 AN: 86054

European-Finnish (FIN) AF: 0.596 AC: 31780 AN: 53358

Middle Eastern (MID) AF: 0.632 AC: 3116 AN: 4934

European-Non Finnish (NFE) AF: 0.614 AC: 678440 AN: 1105520

Other (OTH) AF: 0.573 AC: 34440 AN: 60092

GnomAD4 genome AF: 0.502 AC: 76260 AN: 152004 Hom.: 20825 Cov.: 31 AF XY: 0.499 AC XY: 37069 AN XY: 74296

African (AFR) AF: 0.294 AC: 12191 AN: 41466

American (AMR) AF: 0.446 AC: 6808 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.684 AC: 2373 AN: 3470

East Asian (EAS) AF: 0.358 AC: 1852 AN: 5172

South Asian (SAS) AF: 0.561 AC: 2701 AN: 4814

European-Finnish (FIN) AF: 0.601 AC: 6347 AN: 10552

Middle Eastern (MID) AF: 0.589 AC: 172 AN: 292

European-Non Finnish (NFE) AF: 0.619 AC: 42084 AN: 67942

Other (OTH) AF: 0.528 AC: 1115 AN: 2112

Alfa AF: 0.569 Hom.: 4707

Bravo AF: 0.480

Asia WGS AF: 0.438 AC: 1523 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Neurofibromatosis, type 1 (3)
-	-	3	not provided (3)
-	-	1	Neurofibromatosis, familial spinal (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.21
DANN	Benign	0.57
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2285894; hg19: chr17-29654876; COSMIC: COSV62205010; COSMIC: COSV62205010;