chr11-77883873-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_033547.4(INTS4):​c.2672G>A​(p.Arg891Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,612,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

INTS4
NM_033547.4 missense

Scores

10
5
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.60
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 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.765

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
INTS4NM_033547.4 linkuse as main transcriptc.2672G>A p.Arg891Gln missense_variant 22/23 ENST00000534064.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
INTS4ENST00000534064.6 linkuse as main transcriptc.2672G>A p.Arg891Gln missense_variant 22/231 NM_033547.4 P3Q96HW7-1

Frequencies

GnomAD3 genomes
AF:
0.0000658
AC:
10
AN:
152068
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
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:
0.000118
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000201
AC:
5
AN:
248658
Hom.:
0
AF XY:
0.0000298
AC XY:
4
AN XY:
134432
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000292
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000663
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000889
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.0000301
AC:
44
AN:
1460504
Hom.:
0
Cov.:
31
AF XY:
0.0000330
AC XY:
24
AN XY:
726406
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000815
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000315
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000658
AC:
10
AN:
152068
Hom.:
0
Cov.:
32
AF XY:
0.0000808
AC XY:
6
AN XY:
74256
show subpopulations
Gnomad4 AFR
AF:
0.0000483
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:
0.000118
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000113
Hom.:
0
Bravo
AF:
0.0000416
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0

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 GeneticsSep 29, 2023The c.2672G>A (p.R891Q) alteration is located in exon 22 (coding exon 22) of the INTS4 gene. This alteration results from a G to A substitution at nucleotide position 2672, causing the arginine (R) at amino acid position 891 to be replaced by a glutamine (Q). 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
0.94
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.39
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.41
T;.
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Benign
0.0083
T
MetaRNN
Pathogenic
0.77
D;D
MetaSVM
Uncertain
-0.15
T
MutationAssessor
Benign
1.8
L;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Pathogenic
0.80
T
PROVEAN
Uncertain
-2.6
D;D
REVEL
Uncertain
0.40
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.0060
D;D
Polyphen
1.0
D;.
Vest4
0.90
MutPred
0.56
Loss of sheet (P = 0.0315);.;
MVP
0.57
MPC
1.5
ClinPred
0.99
D
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.73
gMVP
0.64

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: rs745824061; hg19: chr11-77594919; API