17-31232069-T-TTC

Variant names:

• chr17-31232069-T-TTC
• rs864622717
• NM_001042492.3:c.3198-4_3198-3insTC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6_Very_Strong BS2_Supporting

The NM_001042492.3(NF1):​c.3198-4_3198-3insTC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (1 hom., cov: 0)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: NF1 NM_001042492.3 splice_region, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.140
• Publications: 0 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 -9 ACMG points.

• BP6: Variant 17-31232069-T-TTC is Benign according to our data. Variant chr17-31232069-T-TTC is described in ClinVar as Likely_benign. ClinVar VariationId is 413011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 17 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.3198-4_3198-3insTC		splice_region intron	N/A	NP_001035957.1
	NF1	NM_000267.4		c.3198-4_3198-3insTC		splice_region 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.3198-4_3198-3insTC		splice_region intron	N/A	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.3198-4_3198-3insTC		splice_region intron	N/A	ENSP00000348498.3
	NF1	ENST00000579081.6	TSL:1	n.3198-4_3198-3insTC		splice_region intron	N/A	ENSP00000462408.2

Frequencies

GnomAD3 genomes AF: 0.000103 AC: 15 AN: 145988 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000317

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000677

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.000507

GnomAD2 exomes AF: 0.0000320 AC: 5 AN: 156374 AF XY: 0.0000357

Gnomad AFR exome AF: 0.000313

Gnomad AMR exome AF: 0.0000496

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000147

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000146 AC: 17 AN: 1161250 Hom.: 0 Cov.: 3 AF XY: 0.0000120 AC XY: 7 AN XY: 581722

African (AFR) AF: 0.000284 AC: 7 AN: 24614

American (AMR) AF: 0.0000659 AC: 2 AN: 30344

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22380

East Asian (EAS) AF: 0.00 AC: 0 AN: 36184

South Asian (SAS) AF: 0.0000295 AC: 2 AN: 67748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3404

European-Non Finnish (NFE) AF: 0.00000455 AC: 4 AN: 879176

Other (OTH) AF: 0.0000410 AC: 2 AN: 48822

GnomAD4 genome AF: 0.000116 AC: 17 AN: 146058 Hom.: 1 Cov.: 0 AF XY: 0.0000982 AC XY: 7 AN XY: 71290

African (AFR) AF: 0.000369 AC: 14 AN: 37980

American (AMR) AF: 0.0000676 AC: 1 AN: 14798

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.00 AC: 0 AN: 5108

South Asian (SAS) AF: 0.00 AC: 0 AN: 4604

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9816

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 67126

Other (OTH) AF: 0.000501 AC: 1 AN: 1996

Alfa AF: 0.0000487 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype (1)
-	-	1	Neurofibromatosis, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.14
Mutation Taster		=98/2	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs864622717; hg19: chr17-29559087;