4-53379088-A-T

Variant names:

• chr4-53379088-A-T
• NM_030917.4:c.101A>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_030917.4(FIP1L1):​c.101A>T​(p.His34Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,668 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H34R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FIP1L1 NM_030917.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.17

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FIP1L1	NM_030917.4	c.101A>T	p.His34Leu	missense_variant	Exon 2 of 18	ENST00000337488.11	NP_112179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FIP1L1	ENST00000337488.11	c.101A>T	p.His34Leu	missense_variant	Exon 2 of 18	1	NM_030917.4	ENSP00000336752.6
ENSG00000282278	ENST00000507166.5	c.101A>T	p.His34Leu	missense_variant	Exon 2 of 24	2		ENSP00000423325.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461668 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727142

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.099	T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.080
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.44	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.0	N;.
PROVEAN	Benign	-1.7	N;N
REVEL	Uncertain	0.37
Sift	Benign	0.034	D;D
Sift4G	Benign	0.31	T;T
Polyphen		0.0	B;.
Vest4		0.58
MutPred		0.27		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.85
MPC		1.1
ClinPred		0.40	T
GERP RS		4.2
Varity_R		0.15
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-54245255;