rs779199625

Variant names:

• chrX-100824251-G-C
• rs779199625
• NM_001325.3:c.696G>C

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.696G>C​(p.Gln232His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,203,898 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 0.000016 (0 hom. 7 hem.)
• Consequence: CSTF2 NM_001325.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.51
• Publications: 1 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=0.17329317).
• BS2: High Hemizygotes in GnomAdExome4 at 7 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.696G>C	p.Gln232His	missense	Exon 6 of 14	NP_001316.1	P33240-1
	CSTF2	NM_001306206.2		c.696G>C	p.Gln232His	missense	Exon 6 of 15	NP_001293135.1	E7EWR4
	CSTF2	NM_001306209.2		c.696G>C	p.Gln232His	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.696G>C	p.Gln232His	missense	Exon 6 of 14	ENSP00000362063.2	P33240-1
	CSTF2	ENST00000415585.7	TSL:1	c.696G>C	p.Gln232His	missense	Exon 6 of 15	ENSP00000387996.2	E7EWR4
	CSTF2	ENST00000866722.1		c.696G>C	p.Gln232His	missense	Exon 6 of 16	ENSP00000536781.1

Frequencies

GnomAD3 genomes AF: 0.00000890 AC: 1 AN: 112307 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000940

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000859 AC: 15 AN: 174632 AF XY: 0.000100

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000586

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: 0.0000165 AC: 18 AN: 1091591 Hom.: 0 Cov.: 30 AF XY: 0.0000196 AC XY: 7 AN XY: 357505

African (AFR) AF: 0.00 AC: 0 AN: 26099

American (AMR) AF: 0.000529 AC: 18 AN: 34000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19017

East Asian (EAS) AF: 0.00 AC: 0 AN: 30109

South Asian (SAS) AF: 0.00 AC: 0 AN: 52346

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40421

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4101

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 839688

Other (OTH) AF: 0.00 AC: 0 AN: 45810

GnomAD4 genome AF: 0.00000890 AC: 1 AN: 112307 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34463

African (AFR) AF: 0.00 AC: 0 AN: 30864

American (AMR) AF: 0.0000940 AC: 1 AN: 10642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2661

East Asian (EAS) AF: 0.00 AC: 0 AN: 3598

South Asian (SAS) AF: 0.00 AC: 0 AN: 2689

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6162

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53252

Other (OTH) AF: 0.00 AC: 0 AN: 1520

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000330 AC: 4

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	0.20
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.098	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.5
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.010	D
Polyphen		0.99	D
Vest4		0.69
MutPred		0.20		Gain of catalytic residue at L234 (P = 0.0742)
MVP		0.53
MPC		1.4
ClinPred		0.29	T
GERP RS		3.6
Varity_R		0.77
gMVP		0.54
Mutation Taster		=93/7	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: rs779199625; hg19: chrX-100079240;