chr8-144394290-G-A

Variant names:

• chr8-144394290-G-A
• rs1463709761
• NM_013291.3:c.3755C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_013291.3(CPSF1):​c.3755C>T​(p.Pro1252Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,441,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CPSF1 NM_013291.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.31
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814

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.3755C>T	p.Pro1252Leu	missense	Exon 33 of 38	NP_037423.2	Q10570
	MIR939	NR_030635.1		n.-60C>T		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.3755C>T	p.Pro1252Leu	missense	Exon 33 of 38	ENSP00000484669.1	Q10570
	CPSF1	ENST00000620219.4	TSL:1	c.3755C>T	p.Pro1252Leu	missense	Exon 32 of 37	ENSP00000478145.1	Q10570
	CPSF1	ENST00000886816.1		c.3779C>T	p.Pro1260Leu	missense	Exon 33 of 38	ENSP00000556875.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1441704 Hom.: 0 Cov.: 57 AF XY: 0.00 AC XY: 0 AN XY: 714570

African (AFR) AF: 0.00 AC: 0 AN: 32976

American (AMR) AF: 0.00 AC: 0 AN: 42878

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25014

East Asian (EAS) AF: 0.00 AC: 0 AN: 39386

South Asian (SAS) AF: 0.00 AC: 0 AN: 84462

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51676

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5674

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1100292

Other (OTH) AF: 0.00 AC: 0 AN: 59346

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.9	L
PhyloP100		5.3
PrimateAI	Pathogenic	0.81	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.94	P
Vest4		0.81
MutPred		0.60		Loss of disorder (P = 0.0556)
MVP		0.74
ClinPred		0.94	D
GERP RS		5.1
PromoterAI		0.0055	Neutral
Varity_R		0.80
gMVP		0.45
Mutation Taster		=41/59	disease causing

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: rs1463709761; hg19: chr8-145619505;