X-100832774-C-T

Variant names:

• chrX-100832774-C-T
• rs762903224
• NM_001325.3:c.1072C>T
• CSTF2 p.His358Tyr

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001325.3(CSTF2):​c.1072C>T​(p.His358Tyr) variant causes a missense change. 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: 3.60
• 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 3 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.

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.1072C>T	p.His358Tyr	missense	Exon 10 of 14	NP_001316.1	P33240-1
	CSTF2	NM_001306206.2		c.1132C>T	p.His378Tyr	missense	Exon 11 of 15	NP_001293135.1	E7EWR4
	CSTF2	NM_001306209.2		c.1021C>T	p.His341Tyr	missense	Exon 10 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.1072C>T	p.His358Tyr	missense	Exon 10 of 14	ENSP00000362063.2	P33240-1
	CSTF2	ENST00000415585.7	TSL:1	c.1132C>T	p.His378Tyr	missense	Exon 11 of 15	ENSP00000387996.2	E7EWR4
	CSTF2	ENST00000866722.1		c.1219C>T	p.His407Tyr	missense	Exon 12 of 16	ENSP00000536781.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

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	0.11
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.064	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.6
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.10
Sift	Pathogenic	0.0	D
Sift4G	Benign	1.0	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.44
gMVP		0.66
Mutation Taster		=87/13	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs762903224; hg19: chrX-100087763;