NM_007007.3:c.702G>C

Variant names:

• chr12-69258597-G-C
• NM_007007.3:c.702G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_007007.3(CPSF6):​c.702G>C​(p.Gln234His) 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: 31)
• Consequence: CPSF6 NM_007007.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.17
• Publications: 0 publications found

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]

CPSF6 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Broad Center for Mendelian Genomics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29785037).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007007.3. 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
	CPSF6	NM_007007.3	MANE Select	c.702G>C	p.Gln234His	missense	Exon 6 of 10	NP_008938.2	Q16630-1
	CPSF6	NM_001300947.2		c.813G>C	p.Gln271His	missense	Exon 7 of 11	NP_001287876.1	Q16630-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPSF6	ENST00000435070.7	TSL:1 MANE Select	c.702G>C	p.Gln234His	missense	Exon 6 of 10	ENSP00000391774.2	Q16630-1
	CPSF6	ENST00000266679.8	TSL:1	c.813G>C	p.Gln271His	missense	Exon 7 of 11	ENSP00000266679.8	Q16630-2
	CPSF6	ENST00000886662.1		c.849G>C	p.Gln283His	missense	Exon 8 of 12	ENSP00000556721.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

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	Benign	0.17
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.083
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.2
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.062
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.35	T
Polyphen		0.79	P
Vest4		0.51
MutPred		0.36		Loss of solvent accessibility (P = 0.0022)
MVP		0.60
MPC		1.0
ClinPred		0.45	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.069
gMVP		0.24
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

hg19: chr12-69652377;