rs587782218

chr17-31232069-T-C

Variant summary

Our verdict is Benign. Variant got -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, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001383
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: -0.293

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 142080.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Likely_benign=2, Uncertain_significance=1}. Variant chr17-31232069-T-C is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 521 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.3198-4T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000358273.9
NF1	NM_000267.3	c.3198-4T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.3198-4T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001042492.3	P1

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

GnomAD3 exomes AF: 0.00100 AC: 157 AN: 156374 Hom.: 2 AF XY: 0.000678 AC XY: 57 AN XY: 84050

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 SAS exome AF: 0.000473

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

Gnomad4 AFR exome AF: 0.0124

Gnomad4 AMR exome AF: 0.000857

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000829

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.0000412

Gnomad4 NFE exome AF: 0.0000375

Gnomad4 OTH exome AF: 0.000840

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

Gnomad4 AFR AF: 0.0131

Gnomad4 AMR AF: 0.00149

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000652

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000149

Gnomad4 OTH AF: 0.00451

Alfa AF: 0.0000976 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 16, 2017	Variant summary: The NF1 c.3198-4T>C variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 283/181400 control chromosomes in gnomAD, predominantly observed in the African subpopulation at a frequency of 0.014668 (253/17248). This frequency is about 70 times the estimated maximal expected allele frequency of a pathogenic NF1 variant (0.0002084), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	NF1: BS1, BS2 -

Neurofibromatosis, type 1 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 10, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 02, 2017	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 26, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 29, 2015	Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Other data supporting benign classification -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.98
Dann	Benign	0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs587782218; hg19: chr17-29559087; COSMIC: COSV105917502; COSMIC: COSV105917502;