17-31232068-T-C

Variant names:

• chr17-31232068-T-C
• rs587782639
• NM_001042492.3:c.3198-5T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The ENST00000358273.9(NF1):​c.3198-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000238 in 1,258,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: NF1 ENST00000358273.9 splice_region, intron
• Scores: Splicing: ADA: 0.00005474
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.305
• 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 -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 17-31232068-T-C is Benign according to our data. Variant chr17-31232068-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 142679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000358273.9. 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.3198-5T>C		splice_region intron	N/A	NP_001035957.1
	NF1	NM_000267.4		c.3198-5T>C		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.3198-5T>C		splice_region intron	N/A	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.3198-5T>C		splice_region intron	N/A	ENSP00000348498.3
	NF1	ENST00000579081.6	TSL:1	n.3198-5T>C		splice_region intron	N/A	ENSP00000462408.2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.0000129 AC: 2 AN: 155524 AF XY: 0.00

Gnomad AFR exome AF: 0.000105

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000151

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000238 AC: 3 AN: 1258086 Hom.: 0 Cov.: 20 AF XY: 0.00000319 AC XY: 2 AN XY: 626018

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

African (AFR) AF: 0.00 AC: 0 AN: 26586

American (AMR) AF: 0.00 AC: 0 AN: 30404

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23334

East Asian (EAS) AF: 0.00 AC: 0 AN: 36662

South Asian (SAS) AF: 0.00 AC: 0 AN: 70214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48932

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3654

European-Non Finnish (NFE) AF: 0.00000311 AC: 3 AN: 965994

Other (OTH) AF: 0.00 AC: 0 AN: 52306

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0186682), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Neurofibromatosis, type 1 (2)
-	-	2	not specified (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.5
DANN	Benign	0.69
PhyloP100		-0.30

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000055
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.10		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: rs587782639; hg19: chr17-29559086;