11-33087131-C-G

Variant names:

• chr11-33087131-C-G
• rs1855113380
• NM_001326.3:c.1652G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001326.3(CSTF3):​c.1652G>C​(p.Arg551Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CSTF3 NM_001326.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

Genes affected

CSTF3 (HGNC:2485): (cleavage stimulation factor subunit 3) The protein encoded by this gene is one of three (including CSTF1 and CSTF2) cleavage stimulation factors that combine to form the cleavage stimulation factor complex (CSTF). This complex is involved in the polyadenylation and 3' end cleavage of pre-mRNAs. The encoded protein functions as a homodimer and interacts directly with both CSTF1 and CSTF2 in the CSTF complex. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

TCP11L1 (HGNC:25655): (t-complex 11 like 1) Predicted to be involved in signal transduction. Located in microtubule. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSTF3	NM_001326.3	c.1652G>C	p.Arg551Pro	missense_variant	Exon 18 of 21	ENST00000323959.9	NP_001317.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSTF3	ENST00000323959.9	c.1652G>C	p.Arg551Pro	missense_variant	Exon 18 of 21	1	NM_001326.3	ENSP00000315791.4
CSTF3	ENST00000524827.6	c.1748G>C	p.Arg583Pro	missense_variant	Exon 19 of 22	3		ENSP00000431355.2
TCP11L1	ENST00000528962.1	c.352+14478C>G		intron_variant	Intron 2 of 2	3		ENSP00000436471.1
TCP11L1	ENST00000527661.5	n.*78+1933C>G		intron_variant	Intron 12 of 12	5		ENSP00000435667.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1652G>C (p.R551P) alteration is located in exon 18 (coding exon 18) of the CSTF3 gene. This alteration results from a G to C substitution at nucleotide position 1652, causing the arginine (R) at amino acid position 551 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.0091	T
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.6	L;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.7	N;.
REVEL	Benign	0.19
Sift	Benign	0.20	T;.
Sift4G	Benign	0.11	T;.
Polyphen		0.96	D;.
Vest4		0.66
MutPred		0.61		Gain of loop (P = 0.0166);.;
MVP		0.52
MPC		2.2
ClinPred		0.93	D
GERP RS		4.9
Varity_R		0.54
gMVP		0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs1855113380; hg19: chr11-33108677;