14-92134343-G-A

Variant names:

• chr14-92134343-G-A
• NM_017437.3:c.403G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001322271.2(CPSF2):​c.-57G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CPSF2 NM_001322271.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.87

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPSF2	NM_017437.3	c.403G>A	p.Val135Met	missense_variant	Exon 5 of 16	ENST00000298875.9	NP_059133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPSF2	ENST00000298875.9	c.403G>A	p.Val135Met	missense_variant	Exon 5 of 16	1	NM_017437.3	ENSP00000298875.4
CPSF2	ENST00000554290.1	n.*54G>A		non_coding_transcript_exon_variant	Exon 4 of 5	4		ENSP00000452503.1
CPSF2	ENST00000554290.1	n.*54G>A		3_prime_UTR_variant	Exon 4 of 5	4		ENSP00000452503.1
CPSF2	ENST00000553427.5	c.*240G>A		downstream_gene_variant		4		ENSP00000451418.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.403G>A (p.V135M) alteration is located in exon 5 (coding exon 3) of the CPSF2 gene. This alteration results from a G to A substitution at nucleotide position 403, causing the valine (V) at amino acid position 135 to be replaced by a methionine (M). 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	0.34
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.3	M
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.59
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.15	T
Polyphen		0.98	D
Vest4		0.78
MutPred		0.47		Loss of sheet (P = 0.0315);
MVP		0.86
MPC		1.6
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.44
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr14-92600687;