chr2-9443579-C-T

Variant names:

• chr2-9443579-C-T
• rs905530660
• NM_016207.4:c.1160C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_016207.4(CPSF3):​c.1160C>T​(p.Ser387Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 7.57
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862

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.1160C>T	p.Ser387Phe	missense	Exon 10 of 18	NP_057291.1	Q9UKF6
	CPSF3	NM_001321836.2		c.1172C>T	p.Ser391Phe	missense	Exon 11 of 19	NP_001308765.1
	CPSF3	NM_001321833.2		c.1049C>T	p.Ser350Phe	missense	Exon 10 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.1160C>T	p.Ser387Phe	missense	Exon 10 of 18	ENSP00000238112.3	Q9UKF6
	CPSF3	ENST00000460593.1	TSL:1	c.1049C>T	p.Ser350Phe	missense	Exon 10 of 18	ENSP00000418957.1	G5E9W3
	CPSF3	ENST00000882814.1		c.1160C>T	p.Ser387Phe	missense	Exon 10 of 19	ENSP00000552873.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	-0.057	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.50		Loss of disorder (P = 0.0315)
MVP		0.82
MPC		2.1
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.74
gMVP		0.74
Mutation Taster		=35/65	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

dbSNP: rs905530660; hg19: chr2-9583708;