4-53459298-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_030917.4(FIP1L1):c.1638-4C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. 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: 𝑓 0.0055 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0051 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: FIP1L1 NM_030917.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004729
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.272

Genes affected

FIP1L1 (HGNC:19124): (factor interacting with PAPOLA and CPSF1) This gene encodes a subunit of the CPSF (cleavage and polyadenylation specificity factor) complex that polyadenylates the 3' end of mRNA precursors. This gene, the homolog of yeast Fip1 (factor interacting with PAP), binds to U-rich sequences of pre-mRNA and stimulates poly(A) polymerase activity. Its N-terminus contains a PAP-binding site and its C-terminus an RNA-binding domain. An interstitial chromosomal deletion on 4q12 creates an in-frame fusion of human genes FIP1L1 and PDGFRA (platelet-derived growth factor receptor, alpha). The FIP1L1-PDGFRA fusion gene encodes a constitutively activated tyrosine kinase that joins the first 233 amino acids of FIP1L1 to the last 523 amino acids of PDGFRA. This gene fusion and chromosomal deletion is the cause of some forms of idiopathic hypereosinophilic syndrome (HES). This syndrome, recently reclassified as chronic eosinophilic leukemia (CEL), is responsive to treatment with tyrosine kinase inhibitors. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Oct 2008]

LNX1 (HGNC:6657): (ligand of numb-protein X 1) This gene encodes a membrane-bound protein that is involved in signal transduction and protein interactions. The encoded product is an E3 ubiquitin-protein ligase, which mediates ubiquitination and subsequent proteasomal degradation of proteins containing phosphotyrosine binding (PTB) domains. This protein may play an important role in tumorogenesis. Alternatively spliced transcript variants encoding distinct isoforms have been described. A pseudogene, which is located on chromosome 17, has been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 4-53459298-C-T is Benign according to our data. Variant chr4-53459298-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 770711.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FIP1L1	NM_030917.4	c.1638-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000337488.11
LNX1	NM_001126328.3			downstream_gene_variant		ENST00000263925.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FIP1L1	ENST00000337488.11	c.1638-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_030917.4	P4
LNX1	ENST00000263925.8			downstream_gene_variant		1	NM_001126328.3	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 134 AN: 24516 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.00573

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00686

Gnomad ASJ AF: 0.00575

Gnomad EAS AF: 0.00426

Gnomad SAS AF: 0.00239

Gnomad FIN AF: 0.00816

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00515

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00506 AC: 2589 AN: 511184 Hom.: 2 Cov.: 17 AF XY: 0.00593 AC XY: 1504 AN XY: 253568

Gnomad4 AFR exome AF: 0.00423

Gnomad4 AMR exome AF: 0.0153

Gnomad4 ASJ exome AF: 0.00642

Gnomad4 EAS exome AF: 0.00527

Gnomad4 SAS exome AF: 0.0313

Gnomad4 FIN exome AF: 0.00522

Gnomad4 NFE exome AF: 0.00377

Gnomad4 OTH exome AF: 0.00554

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00550 AC: 135 AN: 24526 Hom.: 0 Cov.: 0 AF XY: 0.00586 AC XY: 70 AN XY: 11946

Gnomad4 AFR AF: 0.00571

Gnomad4 AMR AF: 0.00722

Gnomad4 ASJ AF: 0.00575

Gnomad4 EAS AF: 0.00429

Gnomad4 SAS AF: 0.00240

Gnomad4 FIN AF: 0.00816

Gnomad4 NFE AF: 0.00516

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00489 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 25, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.66
Dann	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000047
dbscSNV1_RF	Benign	0.0060
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

Publications

LitVar

Other links and lift over

dbSNP: rs1187998909; hg19: chr4-54325465;