11-61429791-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000340437.8(CPSF7):c.40C>G(p.Pro14Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CPSF7 ENST00000340437.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0320

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.114958435).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPSF7	NM_001142565.3	c.-56+123C>G		intron_variant		ENST00000439958.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPSF7	ENST00000439958.8	c.-56+123C>G		intron_variant		1	NM_001142565.3	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2021

The c.40C>G (p.P14A) alteration is located in exon 1 (coding exon 1) of the CPSF7 gene. This alteration results from a C to G substitution at nucleotide position 40, causing the proline (P) at amino acid position 14 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	16
Dann	Benign	0.86
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.25	T
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	D;D;D;N
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.17
MutPred		0.068		Gain of MoRF binding (P = 0.0351);
MVP		0.19
MPC		0.74
ClinPred		0.21	T
GERP RS		1.2
gMVP		0.18

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

Publications

LitVar

Other links and lift over

dbSNP: rs1861786452; hg19: chr11-61197263;