dbSNP rs199773733: CPSF4L:p.Val40Leu (chr17-73260969-C-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001129885.1(CPSF4L):c.118G>T(p.Val40Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,550,386 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00076 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 7 hom. )

Consequence

CPSF4L
NM_001129885.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.75

Publications

4 publications found

Variant links:

Genes affected

CPSF4L (HGNC:33632): (cleavage and polyadenylation specific factor 4 like) Predicted to enable RNA binding activity and metal ion binding activity. Predicted to be involved in pre-mRNA cleavage required for polyadenylation. Predicted to be part of mRNA cleavage and polyadenylation specificity factor complex. [provided by Alliance of Genome Resources, Apr 2022]

CPSF4L links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.027967423).

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001129885.1. 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
	CPSF4L	NM_001129885.1	MANE Select	c.118G>T	p.Val40Leu	missense	Exon 2 of 6	NP_001123357.1	A6NMK7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CPSF4L	ENST00000344935.8	TSL:1 MANE Select	c.118G>T	p.Val40Leu	missense	Exon 2 of 6	ENSP00000343900.4	A6NMK7
CPSF4L	ENST00000397671.1	TSL:5	c.-75G>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 7	ENSP00000380788.1	H9KVA5
CPSF4L	ENST00000397671.1	TSL:5	c.-75G>T		5_prime_UTR	Exon 2 of 7	ENSP00000380788.1	H9KVA5

Frequencies

GnomAD3 genomes

AF:

0.000756

AC:

115

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.00141

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000707

AC:

109

AN:

154120

AF XY:

0.000660

show subpopulations

Gnomad AFR exome

AF:

0.000126

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.000236

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00154

Gnomad OTH exome

AF:

0.000923

GnomAD4 exome

AF:

0.00171

AC:

2391

AN:

1398136

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

1119

AN XY:

689574

show subpopulations

African (AFR)

AF:

0.000380

AC:

AN:

31560

American (AMR)

AF:

0.000393

AC:

AN:

35658

Ashkenazi Jewish (ASJ)

AF:

0.000199

AC:

AN:

25140

East Asian (EAS)

AF:

0.00

AC:

AN:

35688

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79218

European-Finnish (FIN)

AF:

0.0000204

AC:

AN:

49066

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00210

AC:

2267

AN:

1078182

Other (OTH)

AF:

0.00157

AC:

AN:

57928

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

107

214

321

428

535

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

264

352

440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000755

AC:

115

AN:

152250

Hom.:

Cov.:

AF XY:

0.000766

AC XY:

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41544

American (AMR)

AF:

0.000392

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00141

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00142

Hom.:

Bravo

AF:

0.000808

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.000155

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.011

MetaRNN

Benign

0.028

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.6

PhyloP100

1.7

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.16

Sift

Benign

0.068

Sift4G

Uncertain

0.038

Polyphen

0.076

Vest4

0.22

MutPred

0.31

Loss of sheet (P = 0.0315)

MVP

0.014

ClinPred

0.065

GERP RS

2.0

Varity_R

0.21

gMVP

0.54

Mutation Taster

=297/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over