X-100824216-A-G

Variant names:

• chrX-100824216-A-G
• rs536760362
• NM_001325.3:c.661A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_001325.3(CSTF2):​c.661A>G​(p.Met221Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000677 in 1,210,526 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 26 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000062 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.000068 (0 hom. 23 hem.)
• Consequence: CSTF2 NM_001325.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.08
• 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: Likely_benign. The variant received -5 ACMG points.

• 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=0.08357796).
• BS2: High Hemizygotes in GnomAd4 at 3 XL gene

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.661A>G	p.Met221Val	missense	Exon 6 of 14	NP_001316.1	P33240-1
	CSTF2	NM_001306206.2		c.661A>G	p.Met221Val	missense	Exon 6 of 15	NP_001293135.1	E7EWR4
	CSTF2	NM_001306209.2		c.661A>G	p.Met221Val	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.661A>G	p.Met221Val	missense	Exon 6 of 14	ENSP00000362063.2	P33240-1
	CSTF2	ENST00000415585.7	TSL:1	c.661A>G	p.Met221Val	missense	Exon 6 of 15	ENSP00000387996.2	E7EWR4
	CSTF2	ENST00000866722.1		c.661A>G	p.Met221Val	missense	Exon 6 of 16	ENSP00000536781.1

Frequencies

GnomAD3 genomes AF: 0.0000355 AC: 4 AN: 112529 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000938

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.000654

GnomAD2 exomes AF: 0.0000656 AC: 12 AN: 182844 AF XY: 0.0000446

Gnomad AFR exome AF: 0.0000761

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000734

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000683 AC: 75 AN: 1097943 Hom.: 0 Cov.: 30 AF XY: 0.0000633 AC XY: 23 AN XY: 363309

African (AFR) AF: 0.0000758 AC: 2 AN: 26395

American (AMR) AF: 0.00 AC: 0 AN: 35176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19376

East Asian (EAS) AF: 0.000596 AC: 18 AN: 30197

South Asian (SAS) AF: 0.000166 AC: 9 AN: 54060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40527

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.0000534 AC: 45 AN: 841993

Other (OTH) AF: 0.0000217 AC: 1 AN: 46082

GnomAD4 genome AF: 0.0000622 AC: 7 AN: 112583 Hom.: 0 Cov.: 23 AF XY: 0.0000864 AC XY: 3 AN XY: 34733

African (AFR) AF: 0.000129 AC: 4 AN: 31024

American (AMR) AF: 0.0000937 AC: 1 AN: 10672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

East Asian (EAS) AF: 0.00 AC: 0 AN: 3596

South Asian (SAS) AF: 0.00 AC: 0 AN: 2693

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53311

Other (OTH) AF: 0.000646 AC: 1 AN: 1548

Alfa AF: 0.0000868 Hom.: 1

Bravo AF: 0.0000567

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.000109

EpiControl AF: 0.00

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	0.058
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.024	T
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.1
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.049
Sift	Benign	0.053	T
Sift4G	Benign	0.54	T
Polyphen		0.0	B
Vest4		0.080
MutPred		0.16		Gain of glycosylation at S220 (P = 0.1099)
MVP		0.49
MPC		0.72
ClinPred		0.022	T
GERP RS		4.3
Varity_R		0.31
gMVP		0.17
Mutation Taster		=96/4	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

Other links and lift over

dbSNP: rs536760362; hg19: chrX-100079205; COSMIC: COSV63376226; COSMIC: COSV63376226;