8-144395449-G-A

Variant summary

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

The NM_013291.3(CPSF1):c.3082C>T(p.His1028Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CPSF1 NM_013291.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.75

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]

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/exons	MANE	UniProt
CPSF1	NM_013291.3	c.3082C>T	p.His1028Tyr	missense_variant	27/38	ENST00000616140.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPSF1	ENST00000616140.2	c.3082C>T	p.His1028Tyr	missense_variant	27/38	1	NM_013291.3	P1
CPSF1	ENST00000620219.4	c.3082C>T	p.His1028Tyr	missense_variant	26/37	1		P1
CPSF1	ENST00000529288.1	n.531C>T		non_coding_transcript_exon_variant	1/2	2
CPSF1	ENST00000531042.5	c.388-426C>T		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 44

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2024

The c.3082C>T (p.H1028Y) alteration is located in exon 27 (coding exon 26) of the CPSF1 gene. This alteration results from a C to T substitution at nucleotide position 3082, causing the histidine (H) at amino acid position 1028 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.0092	T
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Benign	1.9	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.80	T
Sift4G	Uncertain	0.0080	D;D
Polyphen		0.53	P;P
Vest4		0.69
MutPred		0.70		Loss of ubiquitination at K1032 (P = 0.1179);Loss of ubiquitination at K1032 (P = 0.1179);
MVP		0.58
ClinPred		0.93	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.30
gMVP		0.83

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-145620664;