chr2-9455713-C-G

Variant names:

• chr2-9455713-C-G
• NM_016207.4:c.1559C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016207.4(CPSF3):​c.1559C>G​(p.Thr520Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CPSF3 NM_016207.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.85
• Publications: 0 publications found

Genes affected

CPSF3 (HGNC:2326): (cleavage and polyadenylation specific factor 3) This gene encodes a member of the metallo-beta-lactamase family. The encoded protein is a 73kDa subunit of the cleavage and polyadenylation specificity factor and functions as an endonuclease that recognizes the pre-mRNA 3'-cleavage site AAUAAA prior to polyadenylation. It also cleaves after the pre-mRNA sequence ACCCA during histone 3'-end pre-mRNA processing. [provided by RefSeq, Oct 2012]

CPSF3 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17965123).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016207.4. 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
	CPSF3	NM_016207.4	MANE Select	c.1559C>G	p.Thr520Ser	missense	Exon 13 of 18	NP_057291.1	Q9UKF6
	CPSF3	NM_001321836.2		c.1571C>G	p.Thr524Ser	missense	Exon 14 of 19	NP_001308765.1
	CPSF3	NM_001321833.2		c.1448C>G	p.Thr483Ser	missense	Exon 13 of 18	NP_001308762.1	G5E9W3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPSF3	ENST00000238112.8	TSL:1 MANE Select	c.1559C>G	p.Thr520Ser	missense	Exon 13 of 18	ENSP00000238112.3	Q9UKF6
	CPSF3	ENST00000460593.1	TSL:1	c.1448C>G	p.Thr483Ser	missense	Exon 13 of 18	ENSP00000418957.1	G5E9W3
	CPSF3	ENST00000882814.1		c.1643C>G	p.Thr548Ser	missense	Exon 14 of 19	ENSP00000552873.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Benign	0.57
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		5.8
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	0.86	T
Polyphen		0.0020	B
Vest4		0.34
MutPred		0.37		Gain of glycosylation at T520 (P = 0.0184)
MVP		0.60
MPC		0.39
ClinPred		0.60	D
GERP RS		5.9
Varity_R		0.052
gMVP		0.41
Mutation Taster		=48/52	disease causing

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

Other links and lift over

hg19: chr2-9595842;