11-77891791-G-C

Variant summary

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

The NM_033547.4(INTS4):ā€‹c.2338C>Gā€‹(p.Leu780Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,692 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

INTS4
NM_033547.4 missense

Scores

7
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.90
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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
INTS4NM_033547.4 linkuse as main transcriptc.2338C>G p.Leu780Val missense_variant 20/23 ENST00000534064.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
INTS4ENST00000534064.6 linkuse as main transcriptc.2338C>G p.Leu780Val missense_variant 20/231 NM_033547.4 P3Q96HW7-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000417
AC:
1
AN:
239526
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
129728
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000302
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1459692
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
726148
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.0000113
ExAC
AF:
0.00000824
AC:
1

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 21, 2021The c.2338C>G (p.L780V) alteration is located in exon 20 (coding exon 20) of the INTS4 gene. This alteration results from a C to G substitution at nucleotide position 2338, causing the leucine (L) at amino acid position 780 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
0.15
BayesDel_addAF
Benign
-0.023
T
BayesDel_noAF
Benign
-0.18
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.089
T;.
Eigen
Uncertain
0.30
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.87
D;D
M_CAP
Benign
0.014
T
MetaRNN
Uncertain
0.48
T;T
MetaSVM
Benign
-0.92
T
MutationAssessor
Benign
2.0
M;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-0.70
N;N
REVEL
Benign
0.13
Sift
Benign
0.24
T;T
Sift4G
Benign
0.30
T;D
Polyphen
0.96
D;.
Vest4
0.80
MutPred
0.24
Gain of catalytic residue at L780 (P = 0.0366);.;
MVP
0.33
MPC
1.2
ClinPred
0.43
T
GERP RS
4.0
Varity_R
0.25
gMVP
0.51

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: rs767731234; hg19: chr11-77602837; API