X-100823307-C-T

Variant names:

• chrX-100823307-C-T
• rs1901148831
• NM_001325.3:c.323C>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001325.3(CSTF2):​c.323C>T​(p.Ala108Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000912 in 1,096,627 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000091 (0 hom. 2 hem.)
• Consequence: CSTF2 NM_001325.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.62

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3123678).
• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSTF2	NM_001325.3	c.323C>T	p.Ala108Val	missense_variant	Exon 4 of 14	ENST00000372972.7	NP_001316.1
CSTF2	NM_001306206.2	c.323C>T	p.Ala108Val	missense_variant	Exon 4 of 15		NP_001293135.1
CSTF2	NM_001306209.2	c.323C>T	p.Ala108Val	missense_variant	Exon 4 of 14		NP_001293138.1
CSTF2	XM_047441854.1	c.323C>T	p.Ala108Val	missense_variant	Exon 4 of 10		XP_047297810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSTF2	ENST00000372972.7	c.323C>T	p.Ala108Val	missense_variant	Exon 4 of 14	1	NM_001325.3	ENSP00000362063.2
CSTF2	ENST00000415585.7	c.323C>T	p.Ala108Val	missense_variant	Exon 4 of 15	1		ENSP00000387996.2
CSTF2	ENST00000413437.1	c.296C>T	p.Ala99Val	missense_variant	Exon 4 of 6	5		ENSP00000415705.1
CSTF2	ENST00000475126.5	n.323C>T		non_coding_transcript_exon_variant	Exon 4 of 14	5		ENSP00000432060.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000912 AC: 10 AN: 1096627 Hom.: 0 Cov.: 29 AF XY: 0.00000552 AC XY: 2 AN XY: 362047

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.323C>T (p.A108V) alteration is located in exon 4 (coding exon 4) of the CSTF2 gene. This alteration results from a C to T substitution at nucleotide position 323, causing the alanine (A) at amino acid position 108 to be replaced by a valine (V). 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	0.19
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.041	.;T;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.3	.;L;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.022	D;D;T
Sift4G	Benign	0.13	T;T;T
Polyphen		0.85	P;P;.
Vest4		0.41
MutPred		0.13		Loss of glycosylation at S113 (P = 0.249);Loss of glycosylation at S113 (P = 0.249);.;
MVP		0.51
MPC		2.8
ClinPred		0.93	D
GERP RS		5.4
Varity_R		0.53
gMVP		0.70

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

LitVar

Other links and lift over

dbSNP: rs1901148831; hg19: chrX-100078296;