chr4-53444114-T-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030917.4. 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
	FIP1L1	NM_030917.4	MANE Select	c.1285+11T>G		intron	N/A	NP_112179.2
	FIP1L1	NM_001376744.1		c.1312+11T>G		intron	N/A	NP_001363673.1
	FIP1L1	NM_001376745.1		c.1312+11T>G		intron	N/A	NP_001363674.1	A0A994J6B4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FIP1L1	ENST00000337488.11	TSL:1 MANE Select	c.1285+11T>G		intron	N/A	ENSP00000336752.6	Q6UN15-1
	ENSG00000282278	ENST00000507166.5	TSL:2	c.1017+18149T>G		intron	N/A	ENSP00000423325.1	A0A0B4J203
	FIP1L1	ENST00000306932.10	TSL:1	c.1063+11T>G		intron	N/A	ENSP00000302993.6	Q6UN15-3

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

GnomAD2 exomes AF: 0.598 AC: 149723 AN: 250550 AF XY: 0.598

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 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

African (AFR) AF: 0.328 AC: 10625 AN: 32354

American (AMR) AF: 0.610 AC: 27191 AN: 44548

Ashkenazi Jewish (ASJ) AF: 0.700 AC: 17967 AN: 25680

East Asian (EAS) AF: 0.468 AC: 18423 AN: 39334

South Asian (SAS) AF: 0.431 AC: 36609 AN: 84968

European-Finnish (FIN) AF: 0.676 AC: 35802 AN: 52954

Middle Eastern (MID) AF: 0.563 AC: 3163 AN: 5614

European-Non Finnish (NFE) AF: 0.665 AC: 701386 AN: 1054312

Other (OTH) AF: 0.611 AC: 35620 AN: 58252

GnomAD4 genome AF: 0.562 AC: 85482 AN: 152050 Hom.: 25640 Cov.: 32 AF XY: 0.562 AC XY: 41759 AN XY: 74292

African (AFR) AF: 0.346 AC: 14364 AN: 41486

American (AMR) AF: 0.635 AC: 9688 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.688 AC: 2386 AN: 3470

East Asian (EAS) AF: 0.448 AC: 2319 AN: 5172

South Asian (SAS) AF: 0.430 AC: 2076 AN: 4826

European-Finnish (FIN) AF: 0.684 AC: 7211 AN: 10546

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.668 AC: 45389 AN: 67970

Other (OTH) AF: 0.581 AC: 1225 AN: 2108

Alfa AF: 0.627 Hom.: 9968

Bravo AF: 0.553

Asia WGS AF: 0.436 AC: 1519 AN: 3470

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.19
DANN	Benign	0.59
PhyloP100		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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