rs587782218

Variant names:

• chr17-31232069-T-C
• rs587782218
• NM_001042492.3:c.3198-4T>C

Your query was ambiguous. Multiple possible variants found:

• chr17-31232069-T-C
• chr17-31232069-T-A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001042492.3(NF1):​c.3198-4T>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 0.00074 in 1,307,288 control chromosomes in the GnomAD database, including 12 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0036 (10 hom., cov: 29)
  • Exomes 𝑓: 0.00038 (2 hom.)
• Consequence: NF1 NM_001042492.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001383
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: -0.293
• 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• 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: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-31232069-T-C is Benign according to our data. Variant chr17-31232069-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 142080.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00364 (531/146058) while in subpopulation AFR AF = 0.0131 (496/37980). AF 95% confidence interval is 0.0121. There are 10 homozygotes in GnomAd4. There are 263 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High AC in GnomAd4 at 531 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	NM_001042492.3	MANE Select	c.3198-4T>C		splice_region intron	N/A	NP_001035957.1	P21359-1
	NF1	NM_000267.4		c.3198-4T>C		splice_region intron	N/A	NP_000258.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.3198-4T>C		splice_region intron	N/A	ENSP00000351015.4	P21359-1
	NF1	ENST00000356175.7	TSL:1	c.3198-4T>C		splice_region intron	N/A	ENSP00000348498.3	P21359-2
	NF1	ENST00000579081.6	TSL:1	n.3198-4T>C		splice_region intron	N/A	ENSP00000462408.2	J3KSB5

Frequencies

GnomAD3 genomes AF: 0.00357 AC: 521 AN: 145988 Hom.: 9 Cov.: 29

Gnomad AFR AF: 0.0128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00149

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000650

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00456

GnomAD2 exomes AF: 0.00100 AC: 157 AN: 156374 AF XY: 0.000678

Gnomad AFR exome AF: 0.0134

Gnomad AMR exome AF: 0.000744

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000851

Gnomad FIN exome AF: 0.0000596

Gnomad NFE exome AF: 0.0000295

Gnomad OTH exome AF: 0.000257

GnomAD4 exome AF: 0.000375 AC: 436 AN: 1161230 Hom.: 2 Cov.: 20 AF XY: 0.000347 AC XY: 202 AN XY: 581706

African (AFR) AF: 0.0124 AC: 304 AN: 24612

American (AMR) AF: 0.000857 AC: 26 AN: 30336

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

East Asian (EAS) AF: 0.0000829 AC: 3 AN: 36184

South Asian (SAS) AF: 0.000325 AC: 22 AN: 67742

European-Finnish (FIN) AF: 0.0000412 AC: 2 AN: 48578

Middle Eastern (MID) AF: 0.00147 AC: 5 AN: 3404

European-Non Finnish (NFE) AF: 0.0000375 AC: 33 AN: 879176

Other (OTH) AF: 0.000840 AC: 41 AN: 48818

GnomAD4 genome AF: 0.00364 AC: 531 AN: 146058 Hom.: 10 Cov.: 29 AF XY: 0.00369 AC XY: 263 AN XY: 71290

African (AFR) AF: 0.0131 AC: 496 AN: 37980

American (AMR) AF: 0.00149 AC: 22 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: 0.000652 AC: 3 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: 0.00451 AC: 9 AN: 1996

Alfa AF: 0.0000976 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	1	1	Neurofibromatosis, type 1 (2)
-	-	2	not specified (2)
-	-	1	Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.98
DANN	Benign	0.73
PhyloP100		-0.29
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.070		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: rs587782218; hg19: chr17-29559087; COSMIC: COSV105917502; COSMIC: COSV105917502;