Variant 8-144393343-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_013291.3(CPSF1):c.4307C>T(p.Thr1436Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,495,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000069 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

CPSF1
NM_013291.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.61

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:

CPSF1 (HGNC:):

CPSF1 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=0.116061896).

BS2

High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPSF1	NM_013291.3 linkuse as main transcript	c.4307C>T	p.Thr1436Met	missense_variant	38/38	ENST00000616140.2	NP_037423.2	Q10570

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CPSF1	ENST00000616140.2 linkuse as main transcript	c.4307C>T	p.Thr1436Met	missense_variant	38/38	1	NM_013291.3	ENSP00000484669.1	Q10570
CPSF1	ENST00000620219.4 linkuse as main transcript	c.4307C>T	p.Thr1436Met	missense_variant	37/37	1		ENSP00000478145.1	Q10570
CPSF1	ENST00000531727.5 linkuse as main transcript	c.590C>T	p.Thr197Met	missense_variant	6/6	3		ENSP00000483775.1	A0A087X101
CPSF1	ENST00000531480.2 linkuse as main transcript	n.675C>T		non_coding_transcript_exon_variant	6/6	3

Frequencies

GnomAD3 genomes

AF:

0.00000693

AC:

AN:

144202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000209

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000387

AC:

AN:

129286

Hom.:

AF XY:

0.0000614

AC XY:

AN XY:

65160

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000350

Gnomad SAS exome

AF:

0.0000672

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000104

AC:

AN:

1351296

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

658750

show subpopulations

Gnomad4 AFR exome

AF:

0.0000643

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000171

Gnomad4 SAS exome

AF:

0.0000703

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.51e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000693

AC:

AN:

144308

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69438

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000210

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

Asia WGS

AF:

0.000577

AC:

AN:

3478

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

Dec 17, 2021

The c.4307C>T (p.T1436M) alteration is located in exon 38 (coding exon 37) of the CPSF1 gene. This alteration results from a C to T substitution at nucleotide position 4307, causing the threonine (T) at amino acid position 1436 to be replaced by a methionine (M). 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

0.051

BayesDel_addAF

Benign

-0.039

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.043

.;T;T

Eigen

Benign

-0.19

Eigen_PC

Benign

0.014

FATHMM_MKL

Uncertain

0.79

M_CAP

Benign

0.0090

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;N;N

PrimateAI

Uncertain

0.66

Sift4G

Benign

0.089

T;D;D

Polyphen

0.0010

.;B;B

Vest4

0.43

MutPred

0.51

.;Loss of disorder (P = 0.1009);Loss of disorder (P = 0.1009);

MVP

0.58

ClinPred

0.23

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.099

gMVP

0.55

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

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