chr1-1312290-C-T

Variant summary

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

The NM_017871.6(INTS11):​c.1543G>A​(p.Val515Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000439 in 1,549,026 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

INTS11
NM_017871.6 missense

Scores

2
6
11

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 4.36
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.1543G>A p.Val515Met missense_variant Exon 15 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.1543G>A p.Val515Met missense_variant Exon 15 of 17 1 NM_017871.6 ENSP00000413493.2 Q5TA45-1

Frequencies

GnomAD3 genomes
AF:
0.0000531
AC:
8
AN:
150644
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000243
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000885
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000192
AC:
3
AN:
156624
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
82770
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000403
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000872
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000166
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000429
AC:
60
AN:
1398382
Hom.:
0
Cov.:
36
AF XY:
0.0000478
AC XY:
33
AN XY:
689808
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000280
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000250
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000426
Gnomad4 OTH exome
AF:
0.0000690
GnomAD4 genome
AF:
0.0000531
AC:
8
AN:
150644
Hom.:
0
Cov.:
33
AF XY:
0.0000410
AC XY:
3
AN XY:
73236
show subpopulations
Gnomad4 AFR
AF:
0.0000243
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000885
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000966
Hom.:
0
Bravo
AF:
0.0000453
ExAC
AF:
0.00000983
AC:
1

ClinVar

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

Submissions by phenotype

Neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities Pathogenic:1
Jun 28, 2023
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

not specified Uncertain:1
Nov 19, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1543G>A (p.V515M) alteration is located in exon 15 (coding exon 15) of the CPSF3L gene. This alteration results from a G to A substitution at nucleotide position 1543, causing the valine (V) at amino acid position 515 to be replaced by a methionine (M). 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
0.29
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.24
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.030
.;.;.;T;T;T;.;.;.
Eigen
Uncertain
0.32
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;D;D;D;D
M_CAP
Benign
0.030
D
MetaRNN
Uncertain
0.59
D;D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
1.9
.;.;.;.;L;.;.;.;.
PrimateAI
Pathogenic
0.81
D
PROVEAN
Benign
-1.5
N;N;.;.;N;N;.;N;N
REVEL
Benign
0.16
Sift
Uncertain
0.0060
D;D;.;.;D;D;.;D;D
Sift4G
Benign
0.066
T;D;D;T;T;D;D;D;T
Polyphen
0.94, 0.97, 0.98, 0.96
.;.;.;.;P;D;.;D;D
Vest4
0.73
MVP
0.65
MPC
0.13
ClinPred
0.61
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.50
gMVP
0.54

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

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

Other links and lift over

dbSNP: rs747481892; hg19: chr1-1247670; COSMIC: COSV105176366; COSMIC: COSV105176366; API