Variant 4-53444114-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_030917.4(FIP1L1):c.1285+11T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.627 in 1,550,066 control chromosomes in the GnomAD database, including 312,414 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.56 ( 25640 hom., cov: 32)

Exomes 𝑓: 0.63 ( 286774 hom. )

Consequence

FIP1L1
NM_030917.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.05

Variant links:

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]

FIP1L1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 4-53444114-T-G is Benign according to our data. Variant chr4-53444114-T-G is described in ClinVar as [Benign]. Clinvar id is 178775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.663 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FIP1L1	NM_030917.4 linkuse as main transcript	c.1285+11T>G		intron_variant		ENST00000337488.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FIP1L1	ENST00000337488.11 linkuse as main transcript	c.1285+11T>G		intron_variant		1	NM_030917.4	P4	Q6UN15-1

Frequencies

GnomAD3 genomes

AF:

0.562

AC:

85447

AN:

151932

Hom.:

25640

Cov.:

show subpopulations

Gnomad AFR

AF:

0.346

Gnomad AMI

AF:

0.724

Gnomad AMR

AF:

0.635

Gnomad ASJ

AF:

0.688

Gnomad EAS

AF:

0.448

Gnomad SAS

AF:

0.431

Gnomad FIN

AF:

0.684

Gnomad MID

AF:

0.566

Gnomad NFE

AF:

0.668

Gnomad OTH

AF:

0.585

GnomAD3 exomes

AF:

0.598

AC:

149723

AN:

250550

Hom.:

46523

AF XY:

0.598

AC XY:

81025

AN XY:

135434

show subpopulations

Gnomad AFR exome

AF:

0.343

Gnomad AMR exome

AF:

0.609

Gnomad ASJ exome

AF:

0.700

Gnomad EAS exome

AF:

0.439

Gnomad SAS exome

AF:

0.434

Gnomad FIN exome

AF:

0.677

Gnomad NFE exome

AF:

0.674

Gnomad OTH exome

AF:

0.634

GnomAD4 exome

AF:

0.634

AC:

886786

AN:

1398016

Hom.:

286774

Cov.:

AF XY:

0.630

AC XY:

440836

AN XY:

699252

show subpopulations

Gnomad4 AFR exome

AF:

0.328

Gnomad4 AMR exome

AF:

0.610

Gnomad4 ASJ exome

AF:

0.700

Gnomad4 EAS exome

AF:

0.468

Gnomad4 SAS exome

AF:

0.431

Gnomad4 FIN exome

AF:

0.676

Gnomad4 NFE exome

AF:

0.665

Gnomad4 OTH exome

AF:

0.611

GnomAD4 genome

AF:

0.562

AC:

85482

AN:

152050

Hom.:

25640

Cov.:

AF XY:

0.562

AC XY:

41759

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.346

Gnomad4 AMR

AF:

0.635

Gnomad4 ASJ

AF:

0.688

Gnomad4 EAS

AF:

0.448

Gnomad4 SAS

AF:

0.430

Gnomad4 FIN

AF:

0.684

Gnomad4 NFE

AF:

0.668

Gnomad4 OTH

AF:

0.581

Alfa

AF:

0.625

Hom.:

5699

Bravo

AF:

0.553

Asia WGS

AF:

0.436

AC:

1519

AN:

3470

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 21, 2013

1285+11T>G in intron 15 of FIP1L1: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus se quence. It has been identified in 35.8% (1576/4406) of African American chromoso mes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs .washington.edu/EVS; dbSNP rs11723755). -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.19

DANN

Benign

0.59

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over