X-100824169-C-T

Variant names:

• chrX-100824169-C-T
• rs1381075460
• NM_001325.3:c.614C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001325.3(CSTF2):​c.614C>T​(p.Pro205Leu) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: CSTF2 NM_001325.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.93
• Publications: 0 publications found

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]

CSTF2 Gene-Disease associations (from GenCC):

• intellectual developmental disorder, X-linked 113

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 3.4292 (above the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to intellectual developmental disorder, X-linked 113.
• BP4: Computational evidence support a benign effect (MetaRNN=0.29286796).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001325.3. 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
	CSTF2	NM_001325.3	MANE Select	c.614C>T	p.Pro205Leu	missense	Exon 6 of 14	NP_001316.1	P33240-1
	CSTF2	NM_001306206.2		c.614C>T	p.Pro205Leu	missense	Exon 6 of 15	NP_001293135.1	E7EWR4
	CSTF2	NM_001306209.2		c.614C>T	p.Pro205Leu	missense	Exon 6 of 14	NP_001293138.1	P33240-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSTF2	ENST00000372972.7	TSL:1 MANE Select	c.614C>T	p.Pro205Leu	missense	Exon 6 of 14	ENSP00000362063.2	P33240-1
	CSTF2	ENST00000415585.7	TSL:1	c.614C>T	p.Pro205Leu	missense	Exon 6 of 15	ENSP00000387996.2	E7EWR4
	CSTF2	ENST00000866722.1		c.614C>T	p.Pro205Leu	missense	Exon 6 of 16	ENSP00000536781.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

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	0.13
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.9
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.045
Sift	Benign	0.14	T
Sift4G	Uncertain	0.038	D
Polyphen		0.24	B
Vest4		0.34
MutPred		0.46		Loss of disorder (P = 0.0344)
MVP		0.75
MPC		1.2
ClinPred		0.93	D
GERP RS		5.4
Varity_R		0.35
gMVP		0.26
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs1381075460; hg19: chrX-100079158; COSMIC: COSV63376152; COSMIC: COSV63376152;