X-100831614-G-A

Variant names:

• chrX-100831614-G-A
• rs1820046975
• NM_001325.3:c.989G>A

Variant summary

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

The NM_001325.3(CSTF2):​c.989G>A​(p.Arg330Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CSTF2 NM_001325.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.21

Genes affected

CSTF2 (HGNC:2484): (cleavage stimulation factor subunit 2) This gene encodes a nuclear protein with an RRM (RNA recognition motif) domain. The protein is a member of the cleavage stimulation factor (CSTF) complex that is involved in the 3' end cleavage and polyadenylation of pre-mRNAs. Specifically, this protein binds GU-rich elements within the 3'-untranslated region of mRNAs. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSTF2	NM_001325.3	c.989G>A	p.Arg330Gln	missense_variant	Exon 9 of 14	ENST00000372972.7	NP_001316.1
CSTF2	NM_001306206.2	c.1049G>A	p.Arg350Gln	missense_variant	Exon 10 of 15		NP_001293135.1
CSTF2	NM_001306209.2	c.938G>A	p.Arg313Gln	missense_variant	Exon 9 of 14		NP_001293138.1
CSTF2	XM_047441854.1	c.*392G>A		downstream_gene_variant			XP_047297810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSTF2	ENST00000372972.7	c.989G>A	p.Arg330Gln	missense_variant	Exon 9 of 14	1	NM_001325.3	ENSP00000362063.2
CSTF2	ENST00000415585.7	c.1049G>A	p.Arg350Gln	missense_variant	Exon 10 of 15	1		ENSP00000387996.2
CSTF2	ENST00000475126.5	n.938G>A		non_coding_transcript_exon_variant	Exon 9 of 14	5		ENSP00000432060.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 09, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.989G>A (p.R330Q) alteration is located in exon 9 (coding exon 9) of the CSTF2 gene. This alteration results from a G to A substitution at nucleotide position 989, causing the arginine (R) at amino acid position 330 to be replaced by a glutamine (Q). 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	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.058	.;T
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	.;M
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0020	D;T
Sift4G	Uncertain	0.026	D;T
Polyphen		1.0	D;D
Vest4		0.63
MutPred		0.24		Loss of methylation at R350 (P = 0.0402);.;
MVP		0.54
MPC		1.3
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.46
gMVP		0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs1820046975; hg19: chrX-100086603;