X-100832853-T-A

Variant names:

• chrX-100832853-T-A
• rs1371328006
• NM_001325.3:c.1151T>A

Variant summary

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

The NM_001325.3(CSTF2):​c.1151T>A​(p.Met384Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000365 in 1,095,578 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000037 (0 hom. 1 hem.)
• Consequence: CSTF2 NM_001325.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.73
• 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.1151T>A	p.Met384Lys	missense	Exon 10 of 14	NP_001316.1	P33240-1
	CSTF2	NM_001306206.2		c.1211T>A	p.Met404Lys	missense	Exon 11 of 15	NP_001293135.1	E7EWR4
	CSTF2	NM_001306209.2		c.1100T>A	p.Met367Lys	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.1151T>A	p.Met384Lys	missense	Exon 10 of 14	ENSP00000362063.2	P33240-1
	CSTF2	ENST00000415585.7	TSL:1	c.1211T>A	p.Met404Lys	missense	Exon 11 of 15	ENSP00000387996.2	E7EWR4
	CSTF2	ENST00000866722.1		c.1298T>A	p.Met433Lys	missense	Exon 12 of 16	ENSP00000536781.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00 AC: 0 AN: 175186 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000365 AC: 4 AN: 1095578 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 1 AN XY: 361096

African (AFR) AF: 0.00 AC: 0 AN: 26372

American (AMR) AF: 0.00 AC: 0 AN: 35016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19341

East Asian (EAS) AF: 0.00 AC: 0 AN: 30162

South Asian (SAS) AF: 0.00 AC: 0 AN: 53502

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40381

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00000476 AC: 4 AN: 840652

Other (OTH) AF: 0.00 AC: 0 AN: 46018

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	Uncertain	0.54
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.7
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.074	T
Polyphen		0.76	P
Vest4		0.70
MutPred		0.25		Gain of ubiquitination at M404 (P = 0.0037)
MVP		0.72
MPC		1.2
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.94
gMVP		0.96
Mutation Taster		=66/34	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: rs1371328006; hg19: chrX-100087842;