4-53444114-T-G

Variant names:

• chr4-53444114-T-G
• rs11723755
• NM_030917.4:c.1285+11T>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.05

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]

ENSG00000282278 (HGNC:):

ACMG classification

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 rank	MANE	Protein	UniProt
FIP1L1	NM_030917.4	c.1285+11T>G		intron_variant	Intron 15 of 17	ENST00000337488.11	NP_112179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FIP1L1	ENST00000337488.11	c.1285+11T>G		intron_variant	Intron 15 of 17	1	NM_030917.4	ENSP00000336752.6
ENSG00000282278	ENST00000507166.5	c.1017+18149T>G		intron_variant	Intron 12 of 23	2		ENSP00000423325.1

Frequencies

GnomAD3 genomes AF: 0.562 AC: 85447 AN: 151932 Hom.: 25640 Cov.: 32

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

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.: 23 AF XY: 0.630 AC XY: 440836 AN XY: 699252

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.: 32 AF XY: 0.562 AC XY: 41759 AN XY: 74292

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

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

Other links and lift over

dbSNP: rs11723755; hg19: chr4-54310281; COSMIC: COSV60998690; COSMIC: COSV60998690;