Genetic Variant CPSF6:p.Val101Ile (chr12-69253081-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_007007.3(CPSF6):c.301G>A(p.Val101Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000371 in 1,590,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

CPSF6
NM_007007.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.38

Publications

1 publications found

Variant links:

Genes affected

CPSF6 (HGNC:13871): (cleavage and polyadenylation specific factor 6) The protein encoded by this gene is one subunit of a cleavage factor required for 3' RNA cleavage and polyadenylation processing. The interaction of the protein with the RNA is one of the earliest steps in the assembly of the 3' end processing complex and facilitates the recruitment of other processing factors. The cleavage factor complex is composed of four polypeptides. This gene encodes the 68kD subunit. It has a domain organization reminiscent of spliceosomal proteins. [provided by RefSeq, Jul 2008]

CPSF6 Gene-Disease associations (from GenCC):

neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Broad Center for Mendelian Genomics

CPSF6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12184271).

BS2

High AC in GnomAdExome4 at 55 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007007.3. 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
	CPSF6	NM_007007.3	MANE Select	c.301G>A	p.Val101Ile	missense	Exon 3 of 10	NP_008938.2	Q16630-1
	CPSF6	NM_001300947.2		c.301G>A	p.Val101Ile	missense	Exon 3 of 11	NP_001287876.1	Q16630-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CPSF6	ENST00000435070.7	TSL:1 MANE Select	c.301G>A	p.Val101Ile	missense	Exon 3 of 10	ENSP00000391774.2	Q16630-1
CPSF6	ENST00000266679.8	TSL:1	c.301G>A	p.Val101Ile	missense	Exon 3 of 11	ENSP00000266679.8	Q16630-2
CPSF6	ENST00000886662.1		c.301G>A	p.Val101Ile	missense	Exon 3 of 12	ENSP00000556721.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000340

AC:

AN:

234998

AF XY:

0.0000393

show subpopulations

Gnomad AFR exome

AF:

0.0000670

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000369

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000382

AC:

AN:

1438366

Hom.:

Cov.:

AF XY:

0.0000461

AC XY:

AN XY:

715362

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32276

American (AMR)

AF:

0.00

AC:

AN:

41894

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25616

East Asian (EAS)

AF:

0.00

AC:

AN:

38380

South Asian (SAS)

AF:

0.000122

AC:

AN:

81688

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52968

Middle Eastern (MID)

AF:

0.000875

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.0000354

AC:

AN:

1100586

Other (OTH)

AF:

0.0000169

AC:

AN:

59246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41430

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10564

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67996

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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:

0.0000329

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

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

0.075

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.080

Eigen

Benign

-0.082

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.013

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.87

MutationAssessor

Benign

-0.36

PhyloP100

6.4

PrimateAI

Uncertain

0.57

PROVEAN

Benign

0.060

REVEL

Benign

0.17

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.21

MVP

0.44

MPC

0.89

ClinPred

0.24

GERP RS

5.2

Varity_R

0.18

gMVP

0.35

Mutation Taster

=66/34

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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