8-144394289-GGG-CAA

Variant names:

• chr8-144394289-GGG-CAA
• NM_013291.3:c.3754_3756delCCCinsTTG
• CPSF1 p.Pro1252Leu

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP2

The NM_013291.3(CPSF1):​c.3754_3756delCCCinsTTG​(p.Pro1252Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CPSF1 NM_013291.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.28
• Publications: 0 publications found

Genes affected

CPSF1 (HGNC:2324): (cleavage and polyadenylation specific factor 1) Cleavage and polyadenylation specificity factor (CPSF) is a multisubunit complex that plays a central role in 3-prime processing of pre-mRNAs. CPSF recognizes the AAUAAA signal in the pre-mRNA and interacts with other proteins to facilitate both RNA cleavage and poly(A) synthesis. CPSF1 is the largest subunit of the CPSF complex (Murthy and Manley, 1995 [PubMed 7590244]).[supplied by OMIM, Mar 2008]

MIR939 (HGNC:33682): (microRNA 939) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Trascript score misZ: 2.0251 (below the threshold of 3.09). GenCC associations: The gene is linked to myopia 27.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013291.3. 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
	CPSF1	NM_013291.3	MANE Select	c.3754_3756delCCCinsTTG	p.Pro1252Leu	missense	N/A	NP_037423.2	Q10570
	MIR939	NR_030635.1		n.-61_-59delCCCinsTTG		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPSF1	ENST00000616140.2	TSL:1 MANE Select	c.3754_3756delCCCinsTTG	p.Pro1252Leu	missense	N/A	ENSP00000484669.1	Q10570
	CPSF1	ENST00000620219.4	TSL:1	c.3754_3756delCCCinsTTG	p.Pro1252Leu	missense	N/A	ENSP00000478145.1	Q10570
	CPSF1	ENST00000886816.1		c.3778_3780delCCCinsTTG	p.Pro1260Leu	missense	N/A	ENSP00000556875.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.3

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr8-145619504;