chr8-144394411-C-T
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BS2_Supporting
The NM_013291.3(CPSF1):c.3712G>A(p.Glu1238Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,609,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
CPSF1
NM_013291.3 missense
NM_013291.3 missense
Scores
6
7
Clinical Significance
Conservation
PhyloP100: 1.13
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.31891525).
BS2
High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CPSF1 | NM_013291.3 | c.3712G>A | p.Glu1238Lys | missense_variant | 32/38 | ENST00000616140.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CPSF1 | ENST00000616140.2 | c.3712G>A | p.Glu1238Lys | missense_variant | 32/38 | 1 | NM_013291.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152204Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000166 AC: 4AN: 240548Hom.: 0 AF XY: 0.0000153 AC XY: 2AN XY: 130684
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GnomAD4 exome AF: 0.00000343 AC: 5AN: 1456824Hom.: 0 Cov.: 56 AF XY: 0.00000276 AC XY: 2AN XY: 724400
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152204Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74344
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 29, 2023 | The c.3712G>A (p.E1238K) alteration is located in exon 32 (coding exon 31) of the CPSF1 gene. This alteration results from a G to A substitution at nucleotide position 3712, causing the glutamic acid (E) at amino acid position 1238 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D
PrimateAI
Uncertain
T
Sift4G
Uncertain
D;D;D
Polyphen
0.73
.;P;P
Vest4
MutPred
0.56
.;Gain of methylation at E1238 (P = 0.025);Gain of methylation at E1238 (P = 0.025);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at