NM_033547.4:c.2672G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_033547.4(INTS4):​c.2672G>C​(p.Arg891Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R891Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

INTS4
NM_033547.4 missense

Scores

11
5
3

Clinical Significance

Not reported in ClinVar

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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.859

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
INTS4NM_033547.4 linkc.2672G>C p.Arg891Pro missense_variant Exon 22 of 23 ENST00000534064.6 NP_291025.3 Q96HW7-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
INTS4ENST00000534064.6 linkc.2672G>C p.Arg891Pro missense_variant Exon 22 of 23 1 NM_033547.4 ENSP00000434466.1 Q96HW7-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1460506
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726408
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.42
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.49
T;.
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.94
D;D
M_CAP
Benign
0.010
T
MetaRNN
Pathogenic
0.86
D;D
MetaSVM
Uncertain
-0.13
T
MutationAssessor
Benign
1.8
L;.
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-4.9
D;D
REVEL
Pathogenic
0.65
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.0030
D;D
Polyphen
1.0
D;.
Vest4
0.97
MutPred
0.59
Loss of sheet (P = 0.0126);.;
MVP
0.65
MPC
2.1
ClinPred
1.0
D
GERP RS
5.2
Varity_R
0.94
gMVP
0.88

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: chr11-77594919; API