NM_017437.3:c.850G>A

Variant names:

• chr14-92143004-G-A
• rs375811121
• NM_017437.3:c.850G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017437.3(CPSF2):​c.850G>A​(p.Val284Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,452,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/26 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CPSF2 NM_017437.3 missense, splice_region
• Scores: Splicing: ADA: 0.5424
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.80
• Publications: 0 publications found

Genes affected

CPSF2 (HGNC:2325): (cleavage and polyadenylation specific factor 2) Predicted to enable RNA binding activity. Involved in mRNA 3'-end processing by stem-loop binding activity and cleavage. Located in membrane. Part of mRNA cleavage and polyadenylation specificity factor complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23562744).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017437.3. 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
	CPSF2	NM_017437.3	MANE Select	c.850G>A	p.Val284Ile	missense splice_region	Exon 9 of 16	NP_059133.1	Q9P2I0
	CPSF2	NM_001322272.2		c.850G>A	p.Val284Ile	missense splice_region	Exon 9 of 16	NP_001309201.1	Q9P2I0
	CPSF2	NM_001322270.2		c.850G>A	p.Val284Ile	missense splice_region	Exon 9 of 15	NP_001309199.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPSF2	ENST00000298875.9	TSL:1 MANE Select	c.850G>A	p.Val284Ile	missense splice_region	Exon 9 of 16	ENSP00000298875.4	Q9P2I0
	CPSF2	ENST00000908829.1		c.850G>A	p.Val284Ile	missense splice_region	Exon 9 of 16	ENSP00000578888.1
	CPSF2	ENST00000932645.1		c.850G>A	p.Val284Ile	missense splice_region	Exon 10 of 17	ENSP00000602704.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247400 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000896

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1452438 Hom.: 0 Cov.: 30 AF XY: 0.00000554 AC XY: 4 AN XY: 721834

African (AFR) AF: 0.00 AC: 0 AN: 33190

American (AMR) AF: 0.00 AC: 0 AN: 44086

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25820

East Asian (EAS) AF: 0.00 AC: 0 AN: 39578

South Asian (SAS) AF: 0.00 AC: 0 AN: 85512

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00000362 AC: 4 AN: 1105324

Other (OTH) AF: 0.00 AC: 0 AN: 59988

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

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	Uncertain	0.41
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Benign	0.36
DEOGEN2	Benign	0.061	T
Eigen	Benign	-0.0080
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.33	N
PhyloP100		9.8
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.26
Sift	Benign	1.0	T
Sift4G	Benign	0.65	T
Polyphen		0.094	B
Vest4		0.45
MVP		0.55
MPC		0.72
ClinPred		0.29	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.24
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.54
dbscSNV1_RF	Benign	0.50
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.20		Position offset: 0

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

Other links and lift over

dbSNP: rs375811121; hg19: chr14-92609348;