11-77891428-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033547.4(INTS4):​c.2483C>T​(p.Ala828Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000049 in 1,613,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

INTS4
NM_033547.4 missense

Scores

1
3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.67
Variant links:
Genes affected
INTS4 (HGNC:25048): (integrator complex subunit 4) INTS4 is a subunit of the Integrator complex, which associates with the C-terminal domain of RNA polymerase II large subunit (POLR2A; MIM 180660) and mediates 3-prime end processing of small nuclear RNAs U1 (RNU1; MIM 180680) and U2 (RNU2; MIM 180690) (Baillat et al., 2005 [PubMed 16239144]).[supplied by OMIM, Mar 2008]
AAMDC (HGNC:30205): (adipogenesis associated Mth938 domain containing) Predicted to be involved in positive regulation of fat cell differentiation. Predicted to act upstream of or within negative regulation of apoptotic process and positive regulation of transcription by RNA polymerase II. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.16810188).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
INTS4NM_033547.4 linkuse as main transcriptc.2483C>T p.Ala828Val missense_variant 21/23 ENST00000534064.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
INTS4ENST00000534064.6 linkuse as main transcriptc.2483C>T p.Ala828Val missense_variant 21/231 NM_033547.4 P3Q96HW7-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152180
Hom.:
0
Cov.:
32
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000200
AC:
5
AN:
250396
Hom.:
0
AF XY:
0.00000739
AC XY:
1
AN XY:
135334
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000545
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000353
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000527
AC:
77
AN:
1461296
Hom.:
0
Cov.:
31
AF XY:
0.0000578
AC XY:
42
AN XY:
726914
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000465
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000630
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152298
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74464
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.0000330
AC:
4

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 15, 2023The c.2483C>T (p.A828V) alteration is located in exon 21 (coding exon 21) of the INTS4 gene. This alteration results from a C to T substitution at nucleotide position 2483, causing the alanine (A) at amino acid position 828 to be replaced by a valine (V). 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
Benign
-0.17
T
BayesDel_noAF
Benign
-0.31
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.064
T;.
Eigen
Benign
-0.22
Eigen_PC
Benign
-0.13
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Benign
0.0093
T
MetaRNN
Benign
0.17
T;T
MetaSVM
Benign
-0.93
T
MutationAssessor
Benign
1.2
L;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-0.99
N;N
REVEL
Benign
0.089
Sift
Benign
0.20
T;T
Sift4G
Benign
0.23
T;D
Polyphen
0.38
B;.
Vest4
0.34
MutPred
0.30
Gain of relative solvent accessibility (P = 0.0289);.;
MVP
0.28
MPC
0.73
ClinPred
0.47
T
GERP RS
4.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.079
gMVP
0.23

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: rs768496944; hg19: chr11-77602474; API