chr11-61419946-C-CA

Variant names:

• chr11-61419946-C-CA
• rs193920985
• ENST00000340437.8:c.654dupT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The ENST00000439958.8(CPSF7):​c.523+2dupT variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CPSF7 ENST00000439958.8 splice_donor, intron
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.87
• Publications: 1 publications found

Genes affected

CPSF7 (HGNC:30098): (cleavage and polyadenylation specific factor 7) Cleavage factor Im (CFIm) is one of six factors necessary for correct cleavage and polyadenylation of pre-mRNAs. CFIm is composed of three different subunits of 25, 59, and 68 kDa, and it functions as a heterotetramer, with a dimer of the 25 kDa subunit binding to two of the 59 or 68 kDa subunits. The protein encoded by this gene represents the 59 kDa subunit, which can interact with the splicing factor U2 snRNP Auxiliary Factor (U2AF) 65 to link the splicing and polyadenylation complexes. [provided by RefSeq, Oct 2016]

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7.7, offset of 28, new splice context is: gggGTacgt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000439958.8. 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
	CPSF7	NM_001142565.3	MANE Select	c.523+2dupT		splice_donor intron	N/A	NP_001136037.1
	CPSF7	NM_024811.4		c.654dupT	p.Glu219fs	frameshift	Exon 5 of 10	NP_079087.3
	CPSF7	NM_001136040.4		c.525dupT	p.Glu176fs	frameshift	Exon 5 of 10	NP_001129512.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPSF7	ENST00000340437.8	TSL:1	c.654dupT	p.Glu219fs	frameshift	Exon 5 of 10	ENSP00000345412.4
	CPSF7	ENST00000439958.8	TSL:1 MANE Select	c.523+2dupT		splice_donor intron	N/A	ENSP00000397203.3
	CPSF7	ENST00000394888.8	TSL:2	c.525dupT	p.Glu176fs	frameshift	Exon 5 of 10	ENSP00000378352.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Prostate cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9

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

dbSNP: rs193920985; hg19: chr11-61187418; COSMIC: COSV61210620; COSMIC: COSV61210620;