8-144393454-T-C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_013291.3(CPSF1):c.4282A>G(p.Ile1428Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000049 in 1,550,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

CPSF1
NM_013291.3 missense, splice_region

Scores

Splicing: ADA: 0.002119

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.74

Variant links:

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]

CPSF1 links:

ADCK5 (HGNC:21738): (aarF domain containing kinase 5) Predicted to enable protein serine/threonine kinase activity. Predicted to be involved in protein phosphorylation. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ADCK5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21612409).

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPSF1	NM_013291.3 link	c.4282A>G	p.Ile1428Val	missense_variant, splice_region_variant	Exon 37 of 38	ENST00000616140.2	NP_037423.2	Q10570
ADCK5	NM_174922.5 link	c.*380T>C		downstream_gene_variant		ENST00000308860.11	NP_777582.4	Q3MIX3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPSF1	ENST00000616140.2 link	c.4282A>G	p.Ile1428Val	missense_variant, splice_region_variant	Exon 37 of 38	1	NM_013291.3	ENSP00000484669.1		Q10570
ADCK5	ENST00000308860.11 link	c.*380T>C		downstream_gene_variant		1	NM_174922.5	ENSP00000310547.6		Q3MIX3

Frequencies

GnomAD3 genomes

AF:

0.0000399

AC:

AN:

150486

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000491

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000591

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000190

AC:

AN:

158266

Hom.:

AF XY:

0.0000238

AC XY:

AN XY:

84078

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000490

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000500

AC:

AN:

1399592

Hom.:

Cov.:

AF XY:

0.0000623

AC XY:

AN XY:

690538

show subpopulations

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:

0.0000630

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000602

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000399

AC:

AN:

150486

Hom.:

Cov.:

AF XY:

0.0000272

AC XY:

AN XY:

73466

show subpopulations

Gnomad4 AFR

AF:

0.0000491

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000591

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000827

Hom.:

Bravo

AF:

0.0000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4282A>G (p.I1428V) alteration is located in exon 37 (coding exon 36) of the CPSF1 gene. This alteration results from a A to G substitution at nucleotide position 4282, causing the isoleucine (I) at amino acid position 1428 to be replaced by a valine (V). 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

Benign

0.14

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.043

.;T;T

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.76

M_CAP

Benign

0.023

MetaRNN

Benign

0.22

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

.;N;N

PrimateAI

Uncertain

0.69

Sift4G

Benign

1.0

T;D;D

Polyphen

0.035

.;B;B

Vest4

0.40

MVP

0.43

ClinPred

0.085

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.17

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0021

dbscSNV1_RF

Benign

0.26

SpliceAI score (max)

0.35

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.35

Position offset: 1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over