rs2001660

Variant names:

• chr2-9473312-T-C
• rs2001660
• NM_016207.4:c.*295T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016207.4(CPSF3):​c.*295T>C variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.585 in 152,018 control chromosomes in the GnomAD database, including 27,498 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.58 (27498 hom., cov: 31)
• Consequence: CPSF3 NM_016207.4 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.797
• Publications: 10 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, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.72 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPSF3	NM_016207.4	MANE Select	c.*295T>C		downstream_gene	N/A	NP_057291.1
	CPSF3	NM_001321836.2		c.*295T>C		downstream_gene	N/A	NP_001308765.1
	CPSF3	NM_001321833.2		c.*295T>C		downstream_gene	N/A	NP_001308762.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPSF3	ENST00000238112.8	TSL:1 MANE Select	c.*295T>C		downstream_gene	N/A	ENSP00000238112.3
	CPSF3	ENST00000460593.1	TSL:1	c.*295T>C		downstream_gene	N/A	ENSP00000418957.1
	CPSF3	ENST00000489403.1	TSL:5	n.*214T>C		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.585 AC: 88796 AN: 151898 Hom.: 27454 Cov.: 31

Gnomad AFR AF: 0.726

Gnomad AMI AF: 0.729

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.673

Gnomad EAS AF: 0.0611

Gnomad SAS AF: 0.446

Gnomad FIN AF: 0.468

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.591

Gnomad OTH AF: 0.605

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.585 AC: 88890 AN: 152018 Hom.: 27498 Cov.: 31 AF XY: 0.571 AC XY: 42393 AN XY: 74278

African (AFR) AF: 0.727 AC: 30142 AN: 41466

American (AMR) AF: 0.442 AC: 6750 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.673 AC: 2338 AN: 3472

East Asian (EAS) AF: 0.0609 AC: 315 AN: 5174

South Asian (SAS) AF: 0.446 AC: 2146 AN: 4810

European-Finnish (FIN) AF: 0.468 AC: 4939 AN: 10548

Middle Eastern (MID) AF: 0.684 AC: 201 AN: 294

European-Non Finnish (NFE) AF: 0.590 AC: 40129 AN: 67958

Other (OTH) AF: 0.600 AC: 1265 AN: 2108

Alfa AF: 0.590 Hom.: 13724

Bravo AF: 0.586

Asia WGS AF: 0.294 AC: 1023 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.0
DANN	Benign	0.37
PhyloP100		-0.80
PromoterAI		0.0047	Neutral

Splicing

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

Other links and lift over

dbSNP: rs2001660; hg19: chr2-9613441;