11-33090671-A-C

Variant names:

• chr11-33090671-A-C
• NM_001326.3:c.1502T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001326.3(CSTF3):​c.1502T>G​(p.Ile501Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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: 9.23

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSTF3	NM_001326.3	c.1502T>G	p.Ile501Arg	missense_variant	Exon 17 of 21	ENST00000323959.9	NP_001317.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSTF3	ENST00000323959.9	c.1502T>G	p.Ile501Arg	missense_variant	Exon 17 of 21	1	NM_001326.3	ENSP00000315791.4
CSTF3	ENST00000524827.6	c.1598T>G	p.Ile533Arg	missense_variant	Exon 18 of 22	3		ENSP00000431355.2
TCP11L1	ENST00000528962.1	c.353-14915A>C		intron_variant	Intron 2 of 2	3		ENSP00000436471.1
TCP11L1	ENST00000527661.5	n.*78+5473A>C		intron_variant	Intron 12 of 12	5		ENSP00000435667.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1502T>G (p.I501R) alteration is located in exon 17 (coding exon 17) of the CSTF3 gene. This alteration results from a T to G substitution at nucleotide position 1502, causing the isoleucine (I) at amino acid position 501 to be replaced by an arginine (R). 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	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.032	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.8	M;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.4	D;.
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0010	D;.
Polyphen		1.0	D;.
Vest4		0.87
MutPred		0.87		Loss of stability (P = 0.0037);.;
MVP		0.77
MPC		3.1
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.94
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-33112217;