12-69262457-C-A

Position:

• chr12-69262457-C-A

Variant summary

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

The NM_007007.3(CPSF6):​c.1554C>A​(p.Asp518Glu) 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. 15/21 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: CPSF6 NM_007007.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.85

Genes affected

CPSF6 (HGNC:13871): (cleavage and polyadenylation specific factor 6) The protein encoded by this gene is one subunit of a cleavage factor required for 3' RNA cleavage and polyadenylation processing. The interaction of the protein with the RNA is one of the earliest steps in the assembly of the 3' end processing complex and facilitates the recruitment of other processing factors. The cleavage factor complex is composed of four polypeptides. This gene encodes the 68kD subunit. It has a domain organization reminiscent of spliceosomal proteins. [provided by RefSeq, Jul 2008]

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=0.07532576).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPSF6	NM_007007.3	c.1554C>A	p.Asp518Glu	missense_variant	9/10	ENST00000435070.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPSF6	ENST00000435070.7	c.1554C>A	p.Asp518Glu	missense_variant	9/10	1	NM_007007.3	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Dec 27, 2022

The c.1554C>A (p.D518E) alteration is located in exon 9 (coding exon 9) of the CPSF6 gene. This alteration results from a C to A substitution at nucleotide position 1554, causing the aspartic acid (D) at amino acid position 518 to be replaced by a glutamic acid (E). 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
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	14
DANN	Benign	0.94
DEOGEN2	Benign	0.068	T;T;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.84	T;D;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.075	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.60	N;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.38	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.36	T;T;T
Sift4G	Benign	0.83	T;T;T
Polyphen		0.0030	B;.;B
Vest4		0.19
MutPred		0.18		Loss of loop (P = 0.0804);.;.;
MVP		0.50
MPC		1.0
ClinPred		0.34	T
GERP RS		-0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.060
gMVP		0.035

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-69656237;