1-1312116-G-T

Variant summary

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

The NM_017871.6(INTS11):​c.1639C>A​(p.Pro547Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000209 in 1,575,368 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P547R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 25)
Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

INTS11
NM_017871.6 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.32
Variant links:
Genes affected
INTS11 (HGNC:26052): (integrator complex subunit 11) The Integrator complex contains at least 12 subunits and associates with the C-terminal domain of RNA polymerase II large subunit (POLR2A; MIM 180660) and mediates the 3-prime end processing of small nuclear RNAs U1 (RNU1; MIM 180680) and U2 (RNU2; MIM 180690). INTS11, or CPSF3L, is the catalytic subunit of the Integrator complex (Baillat et al., 2005 [PubMed 16239144]).[supplied by OMIM, Mar 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
INTS11NM_017871.6 linkc.1639C>A p.Pro547Thr missense_variant Exon 16 of 17 ENST00000435064.6 NP_060341.2 Q5TA45-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
INTS11ENST00000435064.6 linkc.1639C>A p.Pro547Thr missense_variant Exon 16 of 17 1 NM_017871.6 ENSP00000413493.2 Q5TA45-1

Frequencies

GnomAD3 genomes
AF:
0.0000133
AC:
2
AN:
150074
Hom.:
0
Cov.:
25
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000297
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000217
AC:
31
AN:
1425294
Hom.:
0
Cov.:
35
AF XY:
0.0000213
AC XY:
15
AN XY:
704600
show subpopulations
Gnomad4 AFR exome
AF:
0.0000301
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000275
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000133
AC:
2
AN:
150074
Hom.:
0
Cov.:
25
AF XY:
0.00
AC XY:
0
AN XY:
73084
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000297
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000841
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 21, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1639C>A (p.P547T) alteration is located in exon 16 (coding exon 16) of the CPSF3L gene. This alteration results from a C to A substitution at nucleotide position 1639, causing the proline (P) at amino acid position 547 to be replaced by a threonine (T). 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
Benign
0.11
BayesDel_addAF
Uncertain
0.030
T
BayesDel_noAF
Benign
-0.19
CADD
Benign
20
DANN
Benign
0.76
DEOGEN2
Benign
0.0090
.;.;.;T;T;T;.;.;.
Eigen
Benign
-0.096
Eigen_PC
Benign
-0.034
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.96
D;D;D;D;D;D;D;D;D
M_CAP
Benign
0.017
T
MetaRNN
Uncertain
0.60
D;D;D;D;D;D;D;D;D
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.4
.;.;.;.;L;.;.;.;.
PrimateAI
Uncertain
0.73
T
PROVEAN
Benign
-0.14
N;N;.;.;N;N;.;N;N
REVEL
Benign
0.18
Sift
Benign
0.47
T;T;.;.;T;T;.;T;T
Sift4G
Benign
0.41
T;T;T;T;T;T;T;T;T
Polyphen
0.075, 0.14, 0.32, 0.12
.;.;.;.;B;B;.;B;B
Vest4
0.63
MutPred
0.42
.;.;.;.;Gain of catalytic residue at P547 (P = 0.0516);.;.;.;.;
MVP
0.82
MPC
0.033
ClinPred
0.24
T
GERP RS
4.0
Varity_R
0.31
gMVP
0.32

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs746897636; hg19: chr1-1247496; API